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Sample records for ambient igf leading

  1. Lead absorption in cows: biological indicators of ambient lead exposure

    SciTech Connect

    Karacic, V.; Prpic-Majic, D.; Skender, L.

    1984-03-01

    In order to determine actual lead exposure from residual amounts of lead in the environmental soil following the introduction of effective engineering emission controls in a lead smeltery, the absorption of lead in cows grazing in the vicinity was investigated. Four groups of cows were examined: two groups of cows exposed to different ambient lead concentration, compared with two normal groups of cows. In each cow aminolevulinic acid dehydratase (ALAD), erythrocyte protoporphyrin (EP) and blood lead (Pb-B) were determined, two years prior to and four years after the technical sanitation of the lead emission source. The results demonstrated normalization of ALAD, EP and Pb-B after the technical sanitation. In spite of normalization, biological indicators ALAD and Pb-B determined four years after the technical sanitation showed increased lead absorption in comparison with the results of the control group. This indirectly indicates lead contamination of the environment from residual amounts of lead in the soil.

  2. 40 CFR 50.12 - National primary and secondary ambient air quality standards for lead.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... air quality standards for lead. 50.12 Section 50.12 Protection of Environment ENVIRONMENTAL PROTECTION... National primary and secondary ambient air quality standards for lead. (a) National primary and secondary ambient air quality standards for lead and its compounds, measured as elemental lead by a reference...

  3. 40 CFR 50.12 - National primary and secondary ambient air quality standards for lead.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... air quality standards for lead. 50.12 Section 50.12 Protection of Environment ENVIRONMENTAL PROTECTION... National primary and secondary ambient air quality standards for lead. (a) National primary and secondary ambient air quality standards for lead and its compounds, measured as elemental lead by a reference...

  4. 40 CFR 50.12 - National primary and secondary ambient air quality standards for lead.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... air quality standards for lead. 50.12 Section 50.12 Protection of Environment ENVIRONMENTAL PROTECTION... National primary and secondary ambient air quality standards for lead. (a) National primary and secondary ambient air quality standards for lead and its compounds, measured as elemental lead by a reference...

  5. 40 CFR 50.16 - National primary and secondary ambient air quality standards for lead.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... air quality standards for lead. 50.16 Section 50.16 Protection of Environment ENVIRONMENTAL PROTECTION... National primary and secondary ambient air quality standards for lead. (a) The national primary and secondary ambient air quality standards for lead (Pb) and its compounds are 0.15 micrograms per cubic...

  6. 40 CFR 50.16 - National primary and secondary ambient air quality standards for lead.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... air quality standards for lead. 50.16 Section 50.16 Protection of Environment ENVIRONMENTAL PROTECTION... National primary and secondary ambient air quality standards for lead. (a) The national primary and secondary ambient air quality standards for lead (Pb) and its compounds are 0.15 micrograms per cubic...

  7. 40 CFR 50.16 - National primary and secondary ambient air quality standards for lead.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... secondary ambient air quality standards for lead (Pb) and its compounds are 0.15 micrograms per cubic meter, arithmetic mean concentration over a 3-month period, measured in the ambient air as Pb either by: (1) A... primary and secondary ambient air quality standards for Pb are met when the maximum arithmetic...

  8. Decreased IDE and IGF2 expression but increased Aβ40 in the cerebral cortex of mouse pups by early life lead exposure.

    PubMed

    Li, Ning; Yang, Guojun; Wang, Yueying; Qiao, Mingwu; Zhang, Pingan; Shao, Jianfeng; Yang, Guoyu

    2016-03-01

    As the abbreviation of plumbum and a chemical symbol for lead, Pb produces neurotoxic effects, which result into an impairment of learning and memory and other neurological dysfunctions. However, the mechanism of neurotoxicity of Pb exposure is unclear. The present study was undertaken to investigate the effects of maternal lead exposure on expression of insulin-degrading enzyme (IDE),insulin-like growth factor 2 (IGF2) and beta amyloid protein 40 (Aβ40) in the cerebral cortex of mice offspring. Lead exposure initiated from beginning of gestation to weaning. Lead acetate administered in drinking solutions was dissolved in distilled deionized water at the concentrations of 0.1%, 0.2% and 0.5% groups respectively. On the 21st postnatal day, On the PND21, the learning and memory ability were tested by water maze test and the Pb levels were also determined by graphite furnace atomic absorption spectrometry. The expression of IDE, IGF2 and Aβ40 in cerebral cortex was examined by immunohistochemistry, immunofluorescence and western blotting. The lead levels in blood and cerebral cortex of all lead exposure groups were significantly higher than that of the control group (P<0.05). In water maze test, the performances of 0.5% and 1% lead exposure groups were worse than that of the control group (P<0.05).The expression of IDE and IGF2 was decreased, but Aβ40 was increased in lead exposed groups than that of the control group (P<0.05). The decreased expression of IDE and IGF2 and increased expression of Aβ40 in the cerebral cortex of pups may contribute to the neurotoxicity associated with maternal Pb exposure. PMID:26791739

  9. Insulin-like Growth Factor I (IGF-I)-induced Chronic Gliosis and Retinal Stress Lead to Neurodegeneration in a Mouse Model of Retinopathy*

    PubMed Central

    Villacampa, Pilar; Ribera, Albert; Motas, Sandra; Ramírez, Laura; García, Miquel; de la Villa, Pedro; Haurigot, Virginia; Bosch, Fatima

    2013-01-01

    Insulin-like growth factor I (IGF-I) exerts multiple effects on different retinal cell types in both physiological and pathological conditions. Despite the growth factor's extensively described neuroprotective actions, transgenic mice with increased intraocular levels of IGF-I showed progressive impairment of electroretinographic amplitudes up to complete loss of response, with loss of photoreceptors and bipolar, ganglion, and amacrine neurons. Neurodegeneration was preceded by the overexpression of genes related to retinal stress, acute-phase response, and gliosis, suggesting that IGF-I altered normal retinal homeostasis. Indeed, gliosis and microgliosis were present from an early age in transgenic mice, before other alterations occurred, and were accompanied by signs of oxidative stress and impaired glutamate recycling. Older mice also showed overproduction of pro-inflammatory cytokines. Our results suggest that, when chronically increased, intraocular IGF-I is responsible for the induction of deleterious cellular processes that can lead to neurodegeneration, and they highlight the importance that this growth factor may have in the pathogenesis of conditions such as ischemic or diabetic retinopathy. PMID:23620587

  10. Review of proposed EPA ambient lead criteria standard document. Final report. Task assignment No. 10

    SciTech Connect

    Not Available

    1984-03-04

    The proposed October 1983 EPA ambient lead criteria document, Air Quality Criteria for Lead is reviewed from the perspective of DOE's policies and programs and addresses potential impacts on energy production and energy-intensive industries. Following an introduction, the study is organized in five subsequent sections. Section 2.0 addresses environmental and health effects of exposure to lead. Section 3.0 reviews sources of lead emissions. Section 4.0 presents information on lead concentrations in ambient air. Section 5.0 examines dose-effect relationships among lead emissions, ambient air concentrations and blood lead levels. Section 6.0 presents Radian's evaluation of the regulatory implications of the criteria document and the information it provides. 10 figures, 11 tables.

  11. IGF-I and IGF-II effects on local IGF system and signaling pathways in gilthead sea bream (Sparus aurata) cultured myocytes.

    PubMed

    Azizi, Sheida; Nematollahi, Mohammad Ali; Mojazi Amiri, Bagher; Vélez, Emilio J; Salmerón, Cristina; Chan, Shu Jin; Navarro, Isabel; Capilla, Encarnación; Gutiérrez, Joaquim

    2016-06-01

    The insulin-like growth factors (IGFs) have a fundamental role in a vast range of functions acting through a tyrosine-kinase receptor (IGF-IR). IGFs in muscle can affect the expression of components of the local IGF system, myogenic regulatory factors (MRFs), proliferating (proliferating cell nuclear antigen, PCNA) or differentiating molecules (myosin heavy chain, MHC) and, lead to the activation of different signaling pathways. The response of all these genes to IGFs incubation at two different times in day 4 cultured myocytes of gilthead sea bream was analyzed. Both IGFs increased the expression of IGF-I and IGFBP-5, but showed different effects on the receptors, with IGF-I suppressing the expression of both isoforms (IGF-IRa and IGF-IRb) and IGF-II up-regulating only IGF-IRb. Moreover, the protein levels of PCNA and target of rapamycin (TOR) increased after IGF-II incubation, although a decline in Myf5 and a rise in MHC gene expression was caused by IGF-I. Taken together, these results provide evidence for the importance of IGFs on controlling muscle development and growth in gilthead sea bream and suggest that each IGF may be preferentially acting through a specific IGF-IR. Moreover, the data support the hypothesis that IGF-II has a more important role during proliferation, whereas IGF-I seems to be relevant for the differentiation phase of myogenesis. PMID:26602376

  12. Measurements of ambient air lead concentrations in the city of Jeddah, Saudi Arabia

    SciTech Connect

    Abulfaraj, W.H.; Ahmed, M.; Mousli, K.M.; Erturk, F. )

    1990-01-01

    Lead concentrations were determined in six different locations in the Jeddah urban area by atomic absorption spectrometry. Correlations between the air-Pb data and traffic density were investigated. The lead concentration values obtained for the ambient air in Jeddah City ranged from 0.19 {mu}/m{sup 3} to 1.27 {mu}g/m{sup 3}. Comparison with ambient air quality standards from other countries indicates that certain areas in this city are approaching these guideline values.

  13. Relationship between ambient lead concentrations and lead in gasoline in Rio de Janeiro, Brazil

    NASA Astrophysics Data System (ADS)

    Trindade, Helena A.; Pfeiffer, Wolfgang C.

    Lead concentrations were determined in total suspended particulate matter (TSP) from August 1975 to April 1978, in two districts of Rio de Janeiro with different sources of airborne particulate matter. Correlation coefficients between lead content in gasoline and average atmospheric lead concentrations are calculated. Results show a clear effect in the atmosphere if there is a large increase in the lead content of consumed gasoline.

  14. 76 FR 76048 - Air Quality Designations for the 2008 Lead (Pb) National Ambient Air Quality Standards

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-06

    ... From the Federal Register Online via the Government Publishing Office ENVIRONMENTAL PROTECTION AGENCY 40 CFR Part 81 RIN 2060-AR17 Air Quality Designations for the 2008 Lead (Pb) National Ambient Air Quality Standards Correction In rule document 2011-29460 appearing on pages 72097-72120 in the issues...

  15. Do US Ambient Air Lead Levels Have a Significant Impact on Childhood Blood Lead Levels: Results of a National Study

    PubMed Central

    Brink, LuAnn L.; Talbott, Evelyn O.; Sharma, Ravi K.; Marsh, Gary M.; Wu, Wen Chi; Rager, Judith R.; Strosnider, Heather M.

    2013-01-01

    Introduction. Although lead paint and leaded gasoline have not been used in the US for thirty years, thousands of US children continue to have blood lead levels (BLLs) of concern. Methods. We investigated the potential association of modeled air lead levels and BLLs ≥ 10 μg/dL using a large CDC database with BLLs on children aged 0–3 years. Percent of children with BLLs ≥ 10 μg/dL (2000–2007) by county and proportion of pre-50 housing and SES variables were merged with the US EPA's National Air Toxics Assessment (NATA) modeled air lead data. Results. The proportion with BLL ≥ 10 μg/dL was 1.24% in the highest air lead counties, and the proportion with BLL ≥ 10 μg/dL was 0.36% in the lowest air lead counties, resulting in a crude prevalence ratio of 3.4. Further analysis using multivariate negative binomial regression revealed that NATA lead was a significant predictor of % BLL ≥ 10 μg/dL after controlling for percent pre-l950 housing, percent rural, and percent black. A geospatial regression revealed that air lead, percent older housing, and poverty were all significant predictors of % BLL ≥ 10 μg/dL. Conclusions. More emphasis should be given to potential sources of ambient air lead near residential areas. PMID:23983719

  16. 76 FR 20347 - Release of Draft Integrated Review Plan for the National Ambient Air Quality Standards for Lead

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-12

    ... (75 FR 8934). The draft IRP is being made available for consultation with CASAC and for public comment... AGENCY Release of Draft Integrated Review Plan for the National Ambient Air Quality Standards for Lead... National Ambient Air Quality Standards for Lead (draft IRP). This document contains the plans for...

  17. 75 FR 76336 - Notice of Data Availability Regarding Two Studies of Ambient Lead Concentrations Near a General...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-08

    ... AGENCY 40 CFR Part 58 Notice of Data Availability Regarding Two Studies of Ambient Lead Concentrations..., 2009) that revised the primary and secondary National Ambient Air Quality Standards (NAAQS) for lead and associated monitoring requirements. On December 30, 2009, EPA proposed revisions to the...

  18. IGF-I abuse in sport.

    PubMed

    Guha, Nishan; Dashwood, Alexander; Thomas, Nicholas J; Skingle, Alexander J; Sönksen, Peter H; Holt, Richard I G

    2009-09-01

    It is widely believed that growth hormone (GH) is abused by athletes for its anabolic and lipolytic effects. Many of the physiological effects of GH are mediated by the production of insulin-like growth factor-I (IGF-I). Both GH and IGF-I appear on the World Anti-Doping Agency list of prohibited substances. Little is known, however, about the prevalence of abuse with exogenous IGF-I. IGF-I has effects on carbohydrate, lipid and protein metabolism and some of these actions could prove beneficial to competitive athletes. No studies have demonstrated a positive effect of IGF-I on physical performance in healthy individuals but this has not yet been studied in appropriately designed trials. Two pharmaceutical preparations of IGF-I have recently become available for the treatment of growth disorders in children. This availability is likely to increase the prevalence of IGF-I abuse. Combining IGF-I with its binding protein IGFBP-3 in one preparation has the potential to reduce the side-effect profile but the adverse effects of long term IGF-I abuse are currently unknown. Detection of abuse with IGF-I is a major challenge for anti-doping authorities. It is extremely difficult to distinguish the exogenous recombinant form of the hormone from endogenously-produced IGF-I. One approach currently being investigated is based on measuring markers of GH and IGF-I action. This has already proved successful in the fight against GH abuse and, it is hoped, will subsequently lead to a similar test for detection of IGF-I abuse. PMID:20443773

  19. The IGF2 Locus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insulin-like growth factor 2 (IGF2) is a peptide hormone regulating various cellular processes such as proliferation and apoptosis. IGF2 is vital to embryo development. The IGF2 locus covers approximately 150-kb genomic region on human chromosome 11, containing two imprinted genes, IGF2 and H19, sha...

  20. Integrating Susceptibility into Environmental Policy: An Analysis of the National Ambient Air Quality Standard for Lead

    PubMed Central

    Chari, Ramya; Burke, Thomas A.; White, Ronald H.; Fox, Mary A.

    2012-01-01

    Susceptibility to chemical toxins has not been adequately addressed in risk assessment methodologies. As a result, environmental policies may fail to meet their fundamental goal of protecting the public from harm. This study examines how characterization of risk may change when susceptibility is explicitly considered in policy development; in particular we examine the process used by the U.S. Environmental Protection Agency (EPA) to set a National Ambient Air Quality Standard (NAAQS) for lead. To determine a NAAQS, EPA estimated air lead-related decreases in child neurocognitive function through a combination of multiple data elements including concentration-response (CR) functions. In this article, we present alternative scenarios for determining a lead NAAQS using CR functions developed in populations more susceptible to lead toxicity due to socioeconomic disadvantage. The use of CR functions developed in susceptible groups resulted in cognitive decrements greater than original EPA estimates. EPA’s analysis suggested that a standard level of 0.15 µg/m3 would fulfill decision criteria, but by incorporating susceptibility we found that options for the standard could reasonably be extended to lower levels. The use of data developed in susceptible populations would result in the selection of a more protective NAAQS under the same decision framework applied by EPA. Results are used to frame discussion regarding why cumulative risk assessment methodologies are needed to help inform policy development. PMID:22690184

  1. IGF and IGF-binding protein expression in the growth plate of normal, dexamethasone-treated and human IGF-II transgenic mice.

    PubMed

    Smink, J J; Koster, J G; Gresnigt, M G; Rooman, R; Koedam, J A; Van Buul-Offers, S C

    2002-10-01

    Glucocorticoid (GC) treatment in childhood can lead to suppression of longitudinal growth as a side effect. The actions of GCs are thought to be mediated in part by impaired action of the insulin-like growth factors (IGF-I and IGF-II) and their binding proteins (IGFBP-1 to -6). We have studied the effects of GCs on IGF and IGFBP expression at the local level of the growth plate, using non-radioactive in situ hybridization. We treated 3-week-old normal mice for 4 weeks with dexamethasone (DXM). We also treated human IGF-II (hIGF-II) transgenic mice in order to investigate whether IGF-II could protect against the growth retarding effect of this GC. DXM treatment resulted in general growth retardation in both mice strains, however, only in normal mice was tibial length decreased. In both normal and hIGF-II trangenic mice, the total width of the growth plate was not affected, whereas the width of the proliferative zone decreased as a result of the DXM treatment. Additionally, only in normal mice, the width of the hypertrophic zone thickened. Only expression of IGF-I, IGF-II and IGFBP-2 could be detected in the growth plates of 7-week-old normal mice. IGFBP-1, -3, -4, -5 and -6 mRNAs were not detected. DXM treatment of normal mice induced a significant 2.4-fold increase in the number of cells expressing IGF-I mRNA, whereas IGF-II and IGFBP-2 mRNA levels were not affected. In hIGF-II transgenic mice, IGF-I mRNA levels were significantly increased, while endogenous IGF-II and IGFBP-2 mRNAs were unaffected, compared to normal animals. DXM treatment of the hIGF-II transgenic mice induced a further increase of IGF-I mRNA expression, to a similar extent as in DXM-treated normal mice. The increase of IGF-I due to DXM treatment in normal mice might be a reaction in order to minimize the GC-induced growth retardation. Another possibility could be that the increase of IGF-I would contribute to the GC-induced growth retardation by accelerating the differentiation of chondrocytes

  2. 40 CFR Appendix R to Part 50 - Interpretation of the National Ambient Air Quality Standards for Lead

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Pb-PM 10 Data as Surrogate Pb-TSP Data. (a) As stipulated in section 2.10 of Appendix C to 40 CFR... Air Quality Standards for Lead R Appendix R to Part 50 Protection of Environment ENVIRONMENTAL.... 50, App. R Appendix R to Part 50—Interpretation of the National Ambient Air Quality Standards...

  3. A proposed methodology for the assessment of arsenic, nickel, cadmium and lead levels in ambient air.

    PubMed

    Santos, Germán; Fernández-Olmo, Ignacio

    2016-06-01

    Air quality assessment, required by the European Union (EU) Air Quality Directive, Directive 2008/50/EC, is part of the functions attributed to Environmental Management authorities. Based on the cost and time consumption associated with the experimental works required for the air quality assessment in relation to the EU-regulated metal and metalloids, other methods such as modelling or objective estimation arise as competitive alternatives when, in accordance with the Air Quality Directive, the levels of pollutants permit their use at a specific location. This work investigates the possibility of using statistical models based on Partial Least Squares Regression (PLSR) and Artificial Neural Networks (ANNs) to estimate the levels of arsenic (As), cadmium (Cd), nickel (Ni) and lead (Pb) in ambient air and their application for policy purposes. A methodology comprising the main steps that should be taken into consideration to prepare the input database, develop the model and evaluate their performance is proposed and applied to a case of study in Santander (Spain). It was observed that even though these approaches present some difficulties in estimating the individual sample concentrations, having an equivalent performance they can be considered valid for the estimation of the mean values - those to be compared with the limit/target values - fulfilling the uncertainty requirements in the context of the Air Quality Directive. Additionally, the influence of the consideration of input variables related to atmospheric stability on the performance of the studied statistical models has been determined. Although the consideration of these variables as additional inputs had no effect on As and Cd models, they did yield an improvement for Pb and Ni, especially with regard to ANN models. PMID:26950629

  4. 75 FR 71033 - Air Quality Designations for the 2008 Lead (Pb) National Ambient Air Quality Standards

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-22

    ... Agency FR Federal Register FRM Federal Reference Method IQ Intelligence Quotient NAAQS National Ambient..., known as the Tribal Authority Rule (TAR), on February 12, 1999. 63 FR 7254, codified at 40 CFR 49 (1999... a notice on July 8, 2010 (75 FR 39254) which invited the public to comment on EPA's...

  5. 77 FR 12482 - Approval and Promulgation of Air Quality Implementation Plans; Indiana; Lead Ambient Air Quality...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-01

    ... November 12, 2008 (73 FR 66964) and codified at 40 CFR 50.16, ``National primary and secondary ambient air... the Federal Register (73 FR 66964) and codified at 40 CFR 50.16. The primary (health-based) Pb NAAQS... and Budget under Executive Order 12866 (58 FR 51735, October 4, 1993); Does not impose an...

  6. 77 FR 12524 - Approval and Promulgation of Air Quality Implementation Plans; Indiana; Lead Ambient Air Quality...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-01

    ... Ambient Air Quality Standards AGENCY: Environmental Protection Agency (EPA). ACTION: Proposed rule... Maintenance ] Section (AR-18J), U.S. Environmental Protection Agency, 77 West Jackson Boulevard, Chicago...-18J), U.S. Environmental Protection Agency, 77 West Jackson Boulevard, Chicago, Illinois 60604....

  7. Insulin-like growth factor (IGF) and IGF binding protein gene expression in multicystic renal dysplasia.

    PubMed

    Matsell, D G; Bennett, T; Armstrong, R A; Goodyer, P; Goodyer, C; Han, V K

    1997-01-01

    Multicystic dysplastic kidney disease is the most common form of renal dysplasia that leads to ESRD in children. This study describes the histopathological changes of multicystic dysplasia that occur from early fetal life to the postnatal period. At 14 wk gestation, early cystic enlargement of various segments of the nephron have been identified, in addition to a displaced metanephric blastema adjacent to zones of normal nephrogenesis. At later stages, the predominant features include cyst enlargement with marked fibromuscular collars, architectural disorganization, and replacement of the interstitium with a disarray of mesenchymal tissue. This study investigated the expression of the mRNA encoding the insulin-like growth factors (IGF) and IGF binding proteins (IGFBP) and have demonstrated IGF-II, IGFBP-2, and IGFBP-3 to be altered. Apart from their expression in the displaced metanephric blastema, both IGF-II and IGFBP-2 were overexpressed in abnormal tissue elements in all kidneys from fetal to postnatal life. IGF-II gene expression was localized to mesenchymal tissue, specifically in the periductal fibromuscular collars. IGFBP-2 mRNA was found to be expressed exclusively in the cyst epithelia of all cysts at all ages studied, whereas IGFBP-3 mRNA was absent from these epithelia. This study details the failure of normal IGF expression in the development of multicystic renal dysplasia and suggests a role for the IGF system in the progressive histopathological changes of this disorder. PMID:9013452

  8. Small-capacity valve-regulated lead/acid battery with long life at high ambient temperature

    NASA Astrophysics Data System (ADS)

    Hatanaka, T.; Maeda, M.; Iwata, M.

    Valve-regulated lead/acid (VRLA) batteries are widely used as back-up power sources for telecommunications and UPS. These applications require high-reliability under severe environmental conditions. To meet this demand, the authors' company have developed small capacity (12 V, 15-65 A h at C 20/20 rate), long-life VRLA batteries which can endure high ambient temperature. These batteries make use of a new alloy and grid design which has improved resistance to corrosion at the positive plate, while at the same time reduce float current at high temperature. As a result, these batteries have a life expectancy of 13 years at 25°C, and inhibited thermal runaway even under ambient temperatures up to 75°C. The batteries can be installed in outdoor and underground environments.

  9. Insulin-like Growth Factor-II (IGF-II) and IGF-II Analogs with Enhanced Insulin Receptor-a Binding Affinity Promote Neural Stem Cell Expansion*

    PubMed Central

    Ziegler, Amber N.; Chidambaram, Shravanthi; Forbes, Briony E.; Wood, Teresa L.; Levison, Steven W.

    2014-01-01

    The objective of this study was to employ genetically engineered IGF-II analogs to establish which receptor(s) mediate the stemness promoting actions of IGF-II on mouse subventricular zone neural precursors. Neural precursors from the subventricular zone were propagated in vitro in culture medium supplemented with IGF-II analogs. Cell growth and identity were analyzed using sphere generation and further analyzed by flow cytometry. F19A, an analog of IGF-II that does not bind the IGF-2R, stimulated an increase in the proportion of neural stem cells (NSCs) while decreasing the proportion of the later stage progenitors at a lower concentration than IGF-II. V43M, which binds to the IGF-2R with high affinity but which has low binding affinity to the IGF-1R and to the A isoform of the insulin receptor (IR-A) failed to promote NSC growth. The positive effects of F19A on NSC growth were unaltered by the addition of a functional blocking antibody to the IGF-1R. Altogether, these data lead to the conclusion that IGF-II promotes stemness of NSCs via the IR-A and not through activation of either the IGF-1R or the IGF-2R. PMID:24398690

  10. High atmospheric temperatures and 'ambient incubation' drive embryonic development and lead to earlier hatching in a passerine bird.

    PubMed

    Griffith, Simon C; Mainwaring, Mark C; Sorato, Enrico; Beckmann, Christa

    2016-02-01

    Tropical and subtropical species typically experience relatively high atmospheric temperatures during reproduction, and are subject to climate-related challenges that are largely unexplored, relative to more extensive work conducted in temperate regions. We studied the effects of high atmospheric and nest temperatures during reproduction in the zebra finch. We characterized the temperature within nests in a subtropical population of this species in relation to atmospheric temperature. Temperatures within nests frequently exceeded the level at which embryo's develop optimally, even in the absence of parental incubation. We experimentally manipulated internal nest temperature to demonstrate that an average difference of 6°C in the nest temperature during the laying period reduced hatching time by an average of 3% of the total incubation time, owing to 'ambient incubation'. Given the avian constraint of laying a single egg per day, the first eggs of a clutch are subject to prolonged effects of nest temperature relative to later laid eggs, potentially increasing hatching asynchrony. While birds may ameliorate the negative effects of ambient incubation on embryonic development by varying the location and design of their nests, high atmospheric temperatures are likely to constitute an important selective force on avian reproductive behaviour and physiology in subtropical and tropical regions, particularly in the light of predicted climate change that in many areas is leading to a higher frequency of hot days during the periods when birds breed. PMID:26998315

  11. High atmospheric temperatures and ‘ambient incubation’ drive embryonic development and lead to earlier hatching in a passerine bird

    PubMed Central

    Griffith, Simon C.; Mainwaring, Mark C.; Sorato, Enrico; Beckmann, Christa

    2016-01-01

    Tropical and subtropical species typically experience relatively high atmospheric temperatures during reproduction, and are subject to climate-related challenges that are largely unexplored, relative to more extensive work conducted in temperate regions. We studied the effects of high atmospheric and nest temperatures during reproduction in the zebra finch. We characterized the temperature within nests in a subtropical population of this species in relation to atmospheric temperature. Temperatures within nests frequently exceeded the level at which embryo’s develop optimally, even in the absence of parental incubation. We experimentally manipulated internal nest temperature to demonstrate that an average difference of 6°C in the nest temperature during the laying period reduced hatching time by an average of 3% of the total incubation time, owing to ‘ambient incubation’. Given the avian constraint of laying a single egg per day, the first eggs of a clutch are subject to prolonged effects of nest temperature relative to later laid eggs, potentially increasing hatching asynchrony. While birds may ameliorate the negative effects of ambient incubation on embryonic development by varying the location and design of their nests, high atmospheric temperatures are likely to constitute an important selective force on avian reproductive behaviour and physiology in subtropical and tropical regions, particularly in the light of predicted climate change that in many areas is leading to a higher frequency of hot days during the periods when birds breed. PMID:26998315

  12. IGF-1 Gene Expression in Rat Colonic Mucosa After Different Exercise Volumes

    PubMed Central

    Buehlmeyer, Katja; Doering, Frank; Daniel, Hannelore; Petridou, Anatoli; Mougios, Vassilis; Schulz, Thorsten; Michna, Horst

    2007-01-01

    The evidence is increasing for a close link between the insulin/insulin-like growth factor (IGF) system and colon cancer prevention by physical exercise. To reveal exercise-induced alterations in colon mucosa, gene expression of IGF-1 and related genes and serum IGF-1 were investigated. Twenty male Wistar rats performed a 12 week voluntary exercise program. Nine rats served as the control group. Gene expression of IGF-1, IGF-1 receptor (IGF-1R) and IGF-binding protein 3 (IGF-BP3) were quantified by real-time RT-PCR. Circulating IGF-1 was analyzed exercise volume-dependent. Based on 3 distinguished groups with low (L-EX, <2629 m·night-1), medium (M-EX, 3003-7458 m·night-1) and high exercise volume (H-EX, >8314 m·night-1), we observed lower serum IGF-1 levels (P < 0.05) in all exercise groups as compared to the control group and IGF-1 levels declined proportional to the increase in exercise volume. A significant (p < 0.05) positive correlation was found between IGF-1 concentration and body mass (r = 0.50) and a significant negative correlation exists between body mass and exercise volume (r = -0.50). Significant differences in colonic mRNA levels of IGF-1, IGF-1R and IGF-BP3 could not be observed. Based on our data we propose that the exercise as well as the body mass reduction leads to a decrease in circulating IGF-1 and this might represent a prime link to colon cancer prevention. Key pointsThere were significantly lower serum IGF-1 levels in all exercise groups as compared to the control group.GF-1 levels declined proportional to the increase in exercise volume.A significant positive correlation was found between IGF-1 concentration and body mass and a significant negative correlation was found between body mass and exercise volume.Significant differences in colonic mRNA levels of IGF-1, IGF-1R and IGF-BP3 could not be observed. PMID:24149475

  13. IGF-1 Gene Expression in Rat Colonic Mucosa After Different Exercise Volumes.

    PubMed

    Buehlmeyer, Katja; Doering, Frank; Daniel, Hannelore; Petridou, Anatoli; Mougios, Vassilis; Schulz, Thorsten; Michna, Horst

    2007-01-01

    The evidence is increasing for a close link between the insulin/insulin-like growth factor (IGF) system and colon cancer prevention by physical exercise. To reveal exercise-induced alterations in colon mucosa, gene expression of IGF-1 and related genes and serum IGF-1 were investigated. Twenty male Wistar rats performed a 12 week voluntary exercise program. Nine rats served as the control group. Gene expression of IGF-1, IGF-1 receptor (IGF-1R) and IGF-binding protein 3 (IGF-BP3) were quantified by real-time RT-PCR. Circulating IGF-1 was analyzed exercise volume-dependent. Based on 3 distinguished groups with low (L-EX, <2629 m·night(-1)), medium (M-EX, 3003-7458 m·night(-1)) and high exercise volume (H-EX, >8314 m·night(-1)), we observed lower serum IGF-1 levels (P < 0.05) in all exercise groups as compared to the control group and IGF-1 levels declined proportional to the increase in exercise volume. A significant (p < 0.05) positive correlation was found between IGF-1 concentration and body mass (r = 0.50) and a significant negative correlation exists between body mass and exercise volume (r = -0.50). Significant differences in colonic mRNA levels of IGF-1, IGF-1R and IGF-BP3 could not be observed. Based on our data we propose that the exercise as well as the body mass reduction leads to a decrease in circulating IGF-1 and this might represent a prime link to colon cancer prevention. Key pointsThere were significantly lower serum IGF-1 levels in all exercise groups as compared to the control group.GF-1 levels declined proportional to the increase in exercise volume.A significant positive correlation was found between IGF-1 concentration and body mass and a significant negative correlation was found between body mass and exercise volume.Significant differences in colonic mRNA levels of IGF-1, IGF-1R and IGF-BP3 could not be observed. PMID:24149475

  14. Identifying growth hormone-regulated enhancers in the Igf1 locus.

    PubMed

    Alzhanov, Damir; Mukherjee, Aditi; Rotwein, Peter

    2015-11-01

    Growth hormone (GH) plays a central role in regulating somatic growth and in controlling multiple physiological processes in humans and other vertebrates. A key agent in many GH actions is the secreted peptide, IGF-I. As established previously, GH stimulates IGF-I gene expression via the Stat5b transcription factor, leading to production of IGF-I mRNAs and proteins. However, the precise mechanisms by which GH-activated Stat5b promotes IGF-I gene transcription have not been defined. Unlike other GH-regulated genes, there are no Stat5b sites near either of the two IGF-I gene promoters. Although dispersed GH-activated Stat5b binding elements have been mapped in rodent Igf1 gene chromatin, it is unknown how these distal sites might function as potential transcriptional enhancers. Here we have addressed mechanisms of regulation of IGF-I gene transcription by GH by generating cell lines in which the rat Igf1 chromosomal locus has been incorporated into the mouse genome. Using these cells we find that physiological levels of GH rapidly and potently activate Igf1 gene transcription while stimulating physical interactions in chromatin between inducible Stat5b-binding elements and the Igf1 promoters. We have thus developed a robust experimental platform for elucidating how dispersed transcriptional enhancers control Igf1 gene expression under different biological conditions. PMID:26330488

  15. Monocyte/Macrophage-derived IGF-1 Orchestrates Murine Skeletal Muscle Regeneration and Modulates Autocrine Polarization.

    PubMed

    Tonkin, Joanne; Temmerman, Lieve; Sampson, Robert D; Gallego-Colon, Enrique; Barberi, Laura; Bilbao, Daniel; Schneider, Michael D; Musarò, Antonio; Rosenthal, Nadia

    2015-07-01

    Insulin-like growth factor 1 (IGF-1) is a potent enhancer of tissue regeneration, and its overexpression in muscle injury leads to hastened resolution of the inflammatory phase. Here, we show that monocytes/macrophages constitute an important initial source of IGF-1 in muscle injury, as conditional deletion of the IGF-1 gene specifically in mouse myeloid cells (ϕIGF-1 CKO) blocked the normal surge of local IGF-1 in damaged muscle and significantly compromised regeneration. In injured muscle, Ly6C+ monocytes/macrophages and CD206+ macrophages expressed equivalent IGF-1 levels, which were transiently upregulated during transition from the inflammation to repair. In injured ϕIGF-1 CKO mouse muscle, accumulation of CD206+ macrophages was impaired, while an increase in Ly6C+ monocytes/macrophages was favored. Transcriptional profiling uncovered inflammatory skewing in ϕIGF-1 CKO macrophages, which failed to fully induce a reparative gene program in vitro or in vivo, revealing a novel autocrine role for IGF-1 in modulating murine macrophage phenotypes. These data establish local macrophage-derived IGF-1 as a key factor in inflammation resolution and macrophage polarization during muscle regeneration. PMID:25896247

  16. IGF-2R-mediated signaling results in hypertrophy of cultured cardiomyocytes from fetal sheep.

    PubMed

    Wang, Kimberley C W; Brooks, Doug A; Botting, Kimberley J; Morrison, Janna L

    2012-06-01

    Activation of the insulin-like growth factor-1 receptor (IGF-1R) is known to play a role in cardiomyocyte hypertrophy. While IGF-2R is understood to be a clearance receptor for IGF-2, there is also evidence that it may play a role in the induction of pathological cardiomyocyte hypertrophy. It is not known whether IGF-2R activates cardiomyocyte hypertrophy during growth of the fetal heart. Fetal sheep hearts (125 ± 0.4 days gestation) were dissected, and the cardiomyocytes isolated from the left and right ventricles for culturing. Cultured cardiomyocytes were treated with either LONG R(3)IGF-1, an IGF-1R agonist; picropodophyllin, an IGF-1R autophosphorylation inhibitor; U0126, an inhibitor of extracellular signal-regulated protein kinase (ERK); Leu(27)IGF-2, an IGF-2R agonist; Gö6976, a protein kinase C inhibitor; KN-93, an inhibitor of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII); or KN-92, an L-type calcium channel inhibitor and negative control for KN-93. The cross-sectional area of cultured cardiomyocytes was determined relative to control cardiomyocytes treated with serum-free culture medium. IGF-1R and IGF-2R activation each resulted in ERK signaling, but IGF-2R activation alone induced CaMKII signaling, resulting in hypertrophy of cardiomyocytes in the late gestation sheep fetus. These data suggest that changes in the intrauterine environment that result in increased cardiac IGF-2R may also lead to cardiomyocyte hypertrophy in the fetus and potentially an increased risk of cardiovascular disease in adult life. PMID:22441800

  17. Lead

    MedlinePlus

    ... Lead Share Facebook Twitter Google+ Pinterest Contact Us Lead Poisoning is Preventable If your home was built before ... of the RRP rule. Read more . Learn about Lead Poisoning Prevention Week . Report Uncertified Contractors and Environmental Violations ...

  18. Nutritional Regulation of IGFs in Channel Catfish

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We examined changes in hepatic IGF-I and IGF-II mRNA, insulin like growth factor binding proteins (IGFBP-1 and IGFBP-2) mRNA, muscle IGF-I and IGF-II mRNA in fed (fed daily for 45 days) and restricted (not fed for 30 days followed by feeding for 15 days) channel catfish. By day 30, liver IGF-I mRNA...

  19. Evolution of insulin-like growth factor (IGF) function: production and characterization of recombinant hagfish IGF.

    PubMed

    Upton, Z; Francis, G L; Chan, S J; Steiner, D F; Wallace, J C; Ballard, F J

    1997-01-01

    While there is considerable structural evidence that insulin-like growth factors (IGFs) share a long evolutionary history, little is known about the conservation of IGF function. In order to address this, we have made recombinant hagfish IGF, hence allowing characterization of an IGF from a representative of the primitive vertebrate class, Agnatha. The production of recombinant hagfish IGF has been complicated by a number of factors including the requirement of a longer leader peptide for fusion protein expression, reduced solubility of the protein, as well as problems in the refolding procedure. However, we were able to produce a small quantity of hagfish IGF with an N-terminal glycine addition which is biologically active. Furthermore, N-terminal amino acid sequencing and mass spectrometry confirm that we have produced hagfish IGF. In vitro assessment of recombinant hagfish IGF in cultured cells indicates that hagfish IGF indeed shares functional properties with mammalian IGFs. Thus, hagfish IGF stimulates protein synthesis in rat myoblasts, but 20- and 5-fold more peptide, respectively, is required to achieve the same half-maximal responses as with human IGF-I (hIGF-I) or IGF-II (hIGF-II). Hagfish IGF also competes for binding to the type-1 IGF receptor present both on rat myoblasts and on salmon embryo fibroblasts, though with somewhat lower affinity than either hIGF-I or hIGF-II. However, studies investigating binding to the IGF-II-specific type-2 receptor suggest that hagfish IGF may in fact be more closely related to IGF-I than to IGF-II. These results indicate that motifs important for functions associated with mammalian IGFs appear to have evolved prior to the Agnathans diverging from the main line of vertebrate evolution 550 million years ago. Accordingly, we now have functional as well as structural evidence that the IGFs have a long evolutionary history. PMID:9000470

  20. 76 FR 76972 - Release of Final Integrated Review Plan for the National Ambient Air Quality Standards for Lead

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-09

    ... available for public comment (76 FR 20347). The final IRP announced today has been prepared after... was issued on February 26, 2010 (75 FR 8934). Dated: December 5, 2011. Mary E. Henigin, Acting... AGENCY Release of Final Integrated Review Plan for the National Ambient Air Quality Standards for...

  1. 40 CFR Appendix R to Part 50 - Interpretation of the National Ambient Air Quality Standards for Lead

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Pb-PM 10 Data as Surrogate Pb-TSP Data. (a) As stipulated in section 2.10 of Appendix C to 40 CFR... collection periods prior to January 1, 2009 (i.e., “pre-rule” data) will also be considered valid for NAAQS... PROTECTION AGENCY (CONTINUED) AIR PROGRAMS NATIONAL PRIMARY AND SECONDARY AMBIENT AIR QUALITY STANDARDS...

  2. Lead

    MedlinePlus

    ... obvious symptoms, it frequently goes unrecognized. CDC’s Childhood Lead Poisoning Prevention Program is committed to the Healthy People ... Lead Levels Information for Parents Tips for preventing lead poisoning About Us Overview of CDC’s Childhood Lead Poisoning ...

  3. Energy-preserving effects of IGF-1 antagonize starvation-induced cardiac autophagy

    PubMed Central

    Troncoso, Rodrigo; Vicencio, Jose Miguel; Parra, Valentina; Nemchenko, Andriy; Kawashima, Yuki; del Campo, Andrea; Toro, Barbra; Battiprolu, Pavan K.; Aranguiz, Pablo; Chiong, Mario; Yakar, Shoshana; Gillette, Thomas G.; Hill, Joseph A.; Abel, Evan Dale; LeRoith, Derek; Lavandero, Sergio

    2012-01-01

    Aims Insulin-like growth factor 1 (IGF-1) is known to exert cardioprotective actions. However, it remains unknown if autophagy, a major adaptive response to nutritional stress, contributes to IGF-1-mediated cardioprotection. Methods and results We subjected cultured neonatal rat cardiomyocytes, as well as live mice, to nutritional stress and assessed cell death and autophagic rates. Nutritional stress induced by serum/glucose deprivation strongly induced autophagy and cell death, and both responses were inhibited by IGF-1. The Akt/mammalian target of rapamycin (mTOR) pathway mediated the effects of IGF-1 upon autophagy. Importantly, starvation also decreased intracellular ATP levels and oxygen consumption leading to AMP-activated protein kinase (AMPK) activation; IGF-1 increased mitochondrial Ca2+ uptake and mitochondrial respiration in nutrient-starved cells. IGF-1 also rescued ATP levels, reduced AMPK phosphorylation and increased p70S6K phosphorylation, which indicates that in addition to Akt/mTOR, IGF-1 inhibits autophagy by the AMPK/mTOR axis. In mice harbouring a liver-specific igf1 deletion, which dramatically reduces IGF-1 plasma levels, AMPK activity and autophagy were increased, and significant heart weight loss was observed in comparison with wild-type starved animals, revealing the importance of IGF-1 in maintaining cardiac adaptability to nutritional insults in vivo. Conclusion Our data support the cardioprotective actions of IGF-1, which, by rescuing the mitochondrial metabolism and the energetic state of cells, reduces cell death and controls the potentially harmful autophagic response to nutritional challenges. IGF-1, therefore, may prove beneficial to mitigate damage induced by excessive nutrient-related stress, including ischaemic disease in multiple tissues. PMID:22135164

  4. IGF1R mutation analysis in short children with Silver-Russell syndrome features

    PubMed Central

    Soellner, Lukas; Spengler, Sabrina; Begemann, Matthias; Wollmann, Hartmut A.; Binder, Gerhard; Eggermann, Thomas

    2013-01-01

    The insulin-like growth factor 1 receptor (IGF1R) is a key factor in intrauterine and postnatal growth by mediating the biological function of IGF-I. Mutations of IGF1R gene are usually associated with growth retardation, but the clinical picture of IGF1R mutation carriers is heterogeneous. Indeed, these patients show clinical signs compatible with Silver-Russell syndrome (SRS), and some IGF1R mutation carriers have been identified in SRS cohorts. We therefore investigated deoxyribonucleic acid samples of 19 growth-retarded patients with SRS features. Apart from 8 non-pathogenic variants, we detected heterozygosity for the unknown duplication, c.1056_1057dup, leading to a premature termination in one patient and his growth retarded sister. Due to its nature, we assumed that this variant is probably pathogenic. However, the patient and his sister exhibited spontaneous catch-up growth in later life. We therefore hypothesize that the c.1056_1057dup does not result in a significant disruption to the GH-IGFI axis. Thus, this IGF1R mutation without obvious clinical consequence might challenge the actual concept of IGF1R haploinsufficiency as a general cause for disturbed growth in IGF1R mutation carriers. In the future, mutation analysis of IGF1R should be considered in growth-retarded patients with microcephaly and minor SRS features, but not in probands with the characteristic SRS phenotype including macrocephaly.

  5. IGF-I Signaling Is Essential for FSH Stimulation of AKT and Steroidogenic Genes in Granulosa Cells

    PubMed Central

    Zhou, Ping; Baumgarten, Sarah C.; Wu, Yanguang; Bennett, Jill; Winston, Nicola; Hirshfeld-Cytron, Jennifer

    2013-01-01

    FSH and IGF-I synergistically stimulate gonadal steroid production; conversely, silencing the FSH or the IGF-I genes leads to infertility and hypogonadism. To determine the molecular link between these hormones, we examined the signaling cross talk downstream of their receptors. In human and rodent granulosa cells (GCs), IGF-I potentiated the stimulatory effects of FSH and cAMP on the expression of steroidogenic genes. In contrast, inhibition of IGF-I receptor (IGF-IR) activity or expression using pharmacological, genetic, or biochemical approaches prevented the FSH- and cAMP-induced expression of steroidogenic genes and estradiol production. In vivo experiments demonstrated that IGF-IR inactivation reduces the stimulation of steroidogenic genes and follicle growth by gonadotropins. FSH or IGF-I alone stimulated protein kinase B (PKB), which is also known as AKT and in combination synergistically increased AKT phosphorylation. Remarkably, blocking IGF-IR expression or activity decreased AKT basal activity and abolished AKT activation by FSH. In GCs lacking IGF-IR activity, FSH stimulation of Cyp19 expression was rescued by overexpression of constitutively active AKT. Our findings demonstrate, for the first time, that in human, mouse, and rat GCs, the well-known stimulatory effect of FSH on Cyp19 and AKT depends on IGF-I and on the expression and activation of the IGF-IR. PMID:23340251

  6. Comparison of biomass and lipid production under ambient carbon dioxide vigorous aeration and 3% carbon dioxide condition among the lead candidate Chlorella strains screened by various photobioreactor scales.

    PubMed

    Kobayashi, Naoko; Barnes, Austin; Jensen, Travis; Noel, Eric; Andlay, Gunjan; Rosenberg, Julian N; Betenbaugh, Michael J; Guarnieri, Michael T; Oyler, George A

    2015-12-01

    Chlorella species from the UTEX collection, classified by rDNA-based phylogenetic analysis, were screened based on biomass and lipid production in different scales and modes of culture. The lead candidate strains of C. sorokiniana UTEX 1230 and C. vulgaris UTEX 395 and 259 were compared between conditions of vigorous aeration with filtered atmospheric air and 3% CO2 shake-flask cultivation. The biomass of UTEX 1230 produced 2 times higher at 652 mg L(-1) dry weight under both ambient CO2 vigorous aeration and 3% CO2 conditions, while UTEX 395 and 259 under 3% CO2 increased to 3 times higher at 863 mg L(-1) dry weight than ambient CO2 vigorous aeration. The triacylglycerol contents of UTEX 395 and 259 increased more than 30 times to 30% dry weight with 3% CO2, indicating that additional CO2 is essential for both biomass and lipid accumulation in UTEX 395 and 259. PMID:26398668

  7. In situ synthesis of lead sulfide nanoclusters on eggshell membrane fibers by an ambient bio-inspired technique

    NASA Astrophysics Data System (ADS)

    Su, Huilan; Han, Jie; Wang, Na; Dong, Qun; Zhang, Di; Zhang, Chunfu

    2008-02-01

    An ambient aqueous soakage technique is successfully developed to prepare PbS nanoclusters on eggshell membrane (ESM) fibers containing some active functional groups (hydroxyl, amine, imine, etc). Based on the biomaterial ESM serving as the reactive substrate and some ESM biomacromolecules acting as the surfactant, PbS nanocrystallites are in situ formed and further assembled into well-distributed nanoparticle aggregations. This moderate bio-inspired strategy would be of great value in preparing novel functional nanomaterials. The as-prepared hybrid PbS/ESM nanocomposites could have great potential for applications in semiconductor industries, optoelectronic fields, and nanostructured devices.

  8. Targeting the Insulin-Like Growth Factor (IGF) System Is Not as Simple as Just Targeting the Type 1 IGF Receptor.

    PubMed

    Scotlandi, Katia; Belfiore, Antonino

    2012-01-01

    Increased signaling of the insulin-like growth factor (IGF) system via alterations in expression levels of its components has been demonstrated in various tumor types. Numerous experimental studies have supported the involvement of the IGF system signaling axis in tumor initiation and progression. These studies, combined with data that link alterations in the levels of circulating IGFs with cancer risk and prognosis, have focused on the IGF-1 receptor (IGF-1R) as a therapeutic target for patients with cancer. As a consequence, most therapeutic strategies have been designed to specifically inhibit IGF-1R but have for the most part ignored the insulin receptor (IR), based on concerns that targeting IR would lead to unacceptable toxicity both because of its role in physiologic metabolism and because we frequently try to oversimplify biologic complexity whenever we are urged to find practical, friendly solutions for clinical practice. Although this is an understandable and necessary starting point in the complex and long-lasting processes that leads to translational biology, the crude reality of the results obtained from phase I and II studies suggest a need for researchers to be humble and go back to the drawing board. Cancer research has substantially neglected the role of IR, and it remains unclear whether and to what extent avoiding the inhibition of IR has compromised the efficacy of anti-IGF-1R therapy. Clarifying its role might also help us take advantage of older drugs that could offer new perspectives in cancer care. PMID:24451803

  9. 40 CFR Appendix R to Part 50 - Interpretation of the National Ambient Air Quality Standards for Lead

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Pb-PM 10 Data as Surrogate Pb-TSP Data. (a) As stipulated in section 2.10 of Appendix C to 40 CFR... Air Quality Standards for Lead R Appendix R to Part 50 Protection of Environment ENVIRONMENTAL... Lead 1. General. (a) This appendix explains the data handling conventions and computations...

  10. 40 CFR Appendix R to Part 50 - Interpretation of the National Ambient Air Quality Standards for Lead

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Pb-PM 10 Data as Surrogate Pb-TSP Data. (a) As stipulated in section 2.10 of Appendix C to 40 CFR... Air Quality Standards for Lead R Appendix R to Part 50 Protection of Environment ENVIRONMENTAL... Lead 1. General. (a) This appendix explains the data handling conventions and computations...

  11. Comparison of Biomass and Lipid Production under Ambient Carbon Dioxide Vigorous Aeration and 3% Carbon Dioxide Condition Among the Lead Candidate Chlorella Strains Screened by Various Photobioreactor Scales

    SciTech Connect

    Kobayashi, Naoko; Barnes, Austin; Jensen, Travis; Noel, Eric; Andlay, Gunjan; Rosenberg, Julian N.; Betenbaugh, Michael J.; Guarnieri, Michael T.; Oyler, George A.

    2015-09-01

    Chlorella species from the UTEX collection, classified by rDNA-based phylogenetic analysis, were screened based on biomass and lipid production in different scales and modes of culture. Lead candidate strains of C. sorokiniana UTEX 1230 and C. vulgaris UTEX 395 and 259 were compared between conditions of vigorous aeration with filtered atmospheric air and 3% CO2 shake-flask cultivation. We found that the biomass of UTEX 1230 produced 2 times higher at 652 mg L-1 dry weight under both ambient CO2 vigorous aeration and 3% CO2 conditions, while UTEX 395 and 259 under 3% CO2 increased to 3 times higher at 863 mg L-1 dry weight than ambient CO2 vigorous aeration. The triacylglycerol contents of UTEX 395 and 259 increased more than 30 times to 30% dry weight with 3% CO2, indicating that additional CO2 is essential for both biomass and lipid accumulation in UTEX 395 and 259.

  12. An exon splice enhancer primes IGF2:IGF2R binding site structure and function evolution.

    PubMed

    Williams, Christopher; Hoppe, Hans-Jürgen; Rezgui, Dellel; Strickland, Madeleine; Forbes, Briony E; Grutzner, Frank; Frago, Susana; Ellis, Rosamund Z; Wattana-Amorn, Pakorn; Prince, Stuart N; Zaccheo, Oliver J; Nolan, Catherine M; Mungall, Andrew J; Jones, E Yvonne; Crump, Matthew P; Hassan, A Bassim

    2012-11-30

    Placental development and genomic imprinting coevolved with parental conflict over resource distribution to mammalian offspring. The imprinted genes IGF2 and IGF2R code for the growth promoter insulin-like growth factor 2 (IGF2) and its inhibitor, mannose 6-phosphate (M6P)/IGF2 receptor (IGF2R), respectively. M6P/IGF2R of birds and fish do not recognize IGF2. In monotremes, which lack imprinting, IGF2 specifically bound M6P/IGF2R via a hydrophobic CD loop. We show that the DNA coding the CD loop in monotremes functions as an exon splice enhancer (ESE) and that structural evolution of binding site loops (AB, HI, FG) improved therian IGF2 affinity. We propose that ESE evolution led to the fortuitous acquisition of IGF2 binding by M6P/IGF2R that drew IGF2R into parental conflict; subsequent imprinting may then have accelerated affinity maturation. PMID:23197533

  13. Disruption of the protein interaction between FAK and IGF-1R inhibits melanoma tumor growth.

    PubMed

    Ucar, Deniz A; Kurenova, Elena; Garrett, Timothy J; Cance, William G; Nyberg, Carl; Cox, Audrey; Massoll, Nicole; Ostrov, David A; Lawrence, Nicholas; Sebti, Said M; Zajac-Kaye, Maria; Hochwald, Steven N

    2012-09-01

    FAK (focal adhesion kinase) and IGF-1R (insulin-like growth factor receptor-1) directly interact with each other and thereby activate crucial signaling pathways that benefit cancer cells. Inhibition of FAK and IGF-1R function has been shown to significantly decrease cancer cell proliferation and increase sensitivity to chemotherapy and radiation treatment. As a novel approach in human melanoma, we evaluated the effect of a small-molecule compound that disrupts the protein interaction of FAK and IGF-1R. Previously, using virtual screening and functional testing, we identified a lead compound (INT2-31) that targets the known FAK-IGF-1R protein interaction site. We studied the ability of this compound to disrupt FAK-IGF-1R protein interactions, inhibit downstream signaling, decrease human melanoma cell proliferation, alter cell cycle progression, induce apoptosis and decrease tumor growth in vivo. INT2-31 blocked the interaction of FAK and IGF-1R in vitro and in vivo in melanoma cells and tumor xenografts through precluding the activation of IRS-1, leading to reduced phosphorylation of AKT upon IGF-1 stimulation. As a result, INT2-31 significantly inhibited cell proliferation and viability (range 0.05-10 μM). More importantly, 15 mg/kg of INT2-31 given for 21 d via intraperitoneal injection disrupted the interaction of FAK and IGF-1R and effectively decreased phosphorylation of tumor AKT, resulting in significant melanoma tumor regression in vivo. Our data suggest that the FAK-IGF-1R protein interaction is an important target, and disruption of this interaction with a novel small molecule (INT2-31) has potential anti-neoplastic therapeutic effects in human melanoma. PMID:22894899

  14. Characteristics of binding of insulin-like growth factor (IGF)-I and IGF-II analogues to the type 1 IGF receptor determined by BIAcore analysis.

    PubMed

    Forbes, Briony E; Hartfield, Perry J; McNeil, Kerrie A; Surinya, Kathy H; Milner, Steven J; Cosgrove, Leah J; Wallace, John C

    2002-02-01

    Insulin-like growth factor (IGF) binding to the type 1 IGF receptor (IGF1R) elicits mitogenic effects, promotion of differentiation and protection from apoptosis. This study has systematically measured IGF1R binding affinities of IGF-I, IGF-II and 14 IGF analogues to a recombinant high-affinity form of the IGF1R using BIAcore technology. The analogues assessed could be divided into two groups: (a) those designed to investigate binding of IGF-binding protein, which exhibited IGF1R-binding affinities similar to those of IGF-I or IGF-II; (b) those generated to probe IGF1R interactions with greatly reduced IGF1R-binding affinities. The relative binding affinities of IGF-I analogues and IGF-I for the IGF1R determined by BIAcore analysis agreed closely with existing data from receptor-binding assays using cells or tissue membranes, demonstrating that BIAcore technology is a powerful tool for measuring affinities of IGFs for IGF1R. In parallel studies, IGF1R-binding affinities were related to ability to protect against serum withdrawal-induced apoptosis in three different assays including Hoechst 33258 staining, cell survival, and DNA fragmentation assays using the rat pheochromocytoma cell line, PC12. In this model system, IGF-I and IGF-II at low nanomolar concentrations are able to prevent apoptosis completely. We conclude that ability to protect against apoptosis is directly related to ability to bind the IGF1R. PMID:11846798

  15. IGF-2R-Gαq signaling and cardiac hypertrophy in the low-birth-weight lamb.

    PubMed

    Wang, Kimberley C W; Tosh, Darran N; Zhang, Song; McMillen, I Caroline; Duffield, Jaime A; Brooks, Doug A; Morrison, Janna L

    2015-04-01

    The cardiac insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy in a heterotrimeric G protein receptor-coupled manner involving αq (Gαq) or αs (Gαs). We have previously shown increased left ventricular weight and cardiac IGF-2 and IGF-2R gene expression in low-birth-weight (LBW) compared with average-birth-weight (ABW) lambs. Here, we have investigated the cardiac expression of IGF-2 gene variants, the degree of histone acetylation, and the abundance of proteins in the IGF-2R downstream signaling pathway in ABW and LBW lambs. Samples from the left ventricle of ABW and LBW lambs were collected at 21 days of age. There was increased phospho-CaMKII protein with decreased HDAC 4 abundance in the LBW compared with ABW lambs. There was increased GATA 4 and decreased phospho-troponin I abundance in LBW compared with ABW lambs, which are markers of pathological cardiac hypertrophy and impaired or reduced contractility, respectively. There was increased histone acetylation of H3K9 at IGF-2R promoter and IGF-2R intron 2 differentially methylated region in the LBW lamb. In conclusion, histone acetylation of IGF-2R may lead to increased IGF-2R mRNA expression and subsequently mediate Gαq signaling early in life via CaMKII, resulting in an increased risk of left ventricular hypertrophy and cardiovascular disease in adult life. PMID:25632020

  16. IGF-2R-Gαq signaling and cardiac hypertrophy in the low-birth-weight lamb

    PubMed Central

    Wang, Kimberley C. W.; Tosh, Darran N.; Zhang, Song; McMillen, I. Caroline; Duffield, Jaime A.; Brooks, Doug A.

    2015-01-01

    The cardiac insulin-like growth factor 2 receptor (IGF-2R) can induce cardiomyocyte hypertrophy in a heterotrimeric G protein receptor-coupled manner involving αq (Gαq) or αs (Gαs). We have previously shown increased left ventricular weight and cardiac IGF-2 and IGF-2R gene expression in low-birth-weight (LBW) compared with average-birth-weight (ABW) lambs. Here, we have investigated the cardiac expression of IGF-2 gene variants, the degree of histone acetylation, and the abundance of proteins in the IGF-2R downstream signaling pathway in ABW and LBW lambs. Samples from the left ventricle of ABW and LBW lambs were collected at 21 days of age. There was increased phospho-CaMKII protein with decreased HDAC 4 abundance in the LBW compared with ABW lambs. There was increased GATA 4 and decreased phospho-troponin I abundance in LBW compared with ABW lambs, which are markers of pathological cardiac hypertrophy and impaired or reduced contractility, respectively. There was increased histone acetylation of H3K9 at IGF-2R promoter and IGF-2R intron 2 differentially methylated region in the LBW lamb. In conclusion, histone acetylation of IGF-2R may lead to increased IGF-2R mRNA expression and subsequently mediate Gαq signaling early in life via CaMKII, resulting in an increased risk of left ventricular hypertrophy and cardiovascular disease in adult life. PMID:25632020

  17. [Association between IGF system and PAPP-A in coronary atherosclerosis].

    PubMed

    Fierro-Macías, Alfonso Eduardo; Floriano-Sánchez, Esaú; Mena-Burciaga, Victoria Michelle; Gutiérrez-Leonard, Hugo; Lara-Padilla, Eleazar; Abarca-Rojano, Edgar; Fierro-Almanzán, Alfonso Edmundo

    2016-01-01

    Atherosclerosis is a condition that involves multiple pathophysiological mechanisms and whose knowledge has not been fully elucidated. Often, scientific advances on the atherogenic pathophysiology generate that molecules not previously considered in the scene of this disease, were attributed actions on the onset or progression of it. A representative example is the study of a new mechanism involved in the atherogenic process, consisting of the association between the insulin-like growth factor (IGF) system and pregnancy-associated plasma protein-A (PAPP-A). Insulin-like growth factor system is a family of peptides that include 3 peptide hormones, 4 transmembrane receptors and 6 binding proteins. Insulin-like growth factor-1 (IGF-1) is the main ligand of the IGF system involved in coronary atherosclerosis. IGF-1 exerts its effects via activation of the IGF-1R receptor on vascular smooth muscle cells or macrophages. In vascular smooth muscle cells promotes migration and prevents apoptosis which increases plaque stability while in macrophages reduces reverse cholesterol transport leading to the formation of foam cells. Regulation of IGF-1 endothelial bioavailability is carried out by IGFBP proteases, mainly by PAPP-A. In this review, we address the mechanisms between IGF system and PAPP-A in atherosclerosis with emphasis on molecular effects on vascular smooth muscle cells and macrophages. PMID:26906607

  18. Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS.

    PubMed

    Allodi, Ilary; Comley, Laura; Nichterwitz, Susanne; Nizzardo, Monica; Simone, Chiara; Benitez, Julio Aguila; Cao, Ming; Corti, Stefania; Hedlund, Eva

    2016-01-01

    The fatal disease amyotrophic lateral sclerosis (ALS) is characterized by the loss of somatic motor neurons leading to muscle wasting and paralysis. However, motor neurons in the oculomotor nucleus, controlling eye movement, are for unknown reasons spared. We found that insulin-like growth factor 2 (IGF-2) was maintained in oculomotor neurons in ALS and thus could play a role in oculomotor resistance in this disease. We also showed that IGF-1 receptor (IGF-1R), which mediates survival pathways upon IGF binding, was highly expressed in oculomotor neurons and on extraocular muscle endplate. The addition of IGF-2 induced Akt phosphorylation, glycogen synthase kinase-3β phosphorylation and β-catenin levels while protecting ALS patient motor neurons. IGF-2 also rescued motor neurons derived from spinal muscular atrophy (SMA) patients from degeneration. Finally, AAV9::IGF-2 delivery to muscles of SOD1(G93A) ALS mice extended life-span by 10%, while preserving motor neurons and inducing motor axon regeneration. Thus, our studies demonstrate that oculomotor-specific expression can be utilized to identify candidates that protect vulnerable motor neurons from degeneration. PMID:27180807

  19. Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS

    PubMed Central

    Allodi, Ilary; Comley, Laura; Nichterwitz, Susanne; Nizzardo, Monica; Simone, Chiara; Benitez, Julio Aguila; Cao, Ming; Corti, Stefania; Hedlund, Eva

    2016-01-01

    The fatal disease amyotrophic lateral sclerosis (ALS) is characterized by the loss of somatic motor neurons leading to muscle wasting and paralysis. However, motor neurons in the oculomotor nucleus, controlling eye movement, are for unknown reasons spared. We found that insulin-like growth factor 2 (IGF-2) was maintained in oculomotor neurons in ALS and thus could play a role in oculomotor resistance in this disease. We also showed that IGF-1 receptor (IGF-1R), which mediates survival pathways upon IGF binding, was highly expressed in oculomotor neurons and on extraocular muscle endplate. The addition of IGF-2 induced Akt phosphorylation, glycogen synthase kinase-3β phosphorylation and β-catenin levels while protecting ALS patient motor neurons. IGF-2 also rescued motor neurons derived from spinal muscular atrophy (SMA) patients from degeneration. Finally, AAV9::IGF-2 delivery to muscles of SOD1G93A ALS mice extended life-span by 10%, while preserving motor neurons and inducing motor axon regeneration. Thus, our studies demonstrate that oculomotor-specific expression can be utilized to identify candidates that protect vulnerable motor neurons from degeneration. PMID:27180807

  20. Regulation of Ligand and Shear Stress-induced Insulin-like Growth Factor 1 (IGF1) Signaling by the Integrin Pathway.

    PubMed

    Tahimic, Candice G T; Long, Roger K; Kubota, Takuo; Sun, Maggie Yige; Elalieh, Hashem; Fong, Chak; Menendez, Alicia T; Wang, Yongmei; Vilardaga, Jean-Pierre; Bikle, Daniel D

    2016-04-01

    Mechanical loading of the skeleton, as achieved during daily movement and exercise, preserves bone mass and stimulates bone formation, whereas skeletal unloading from prolonged immobilization leads to bone loss. A functional interplay between the insulin-like growth factor 1 receptor (IGF1R), a major player in skeletal development, and integrins, mechanosensors, is thought to regulate the anabolic response of osteogenic cells to mechanical load. The mechanistic basis for this cross-talk is unclear. Here we report that integrin signaling regulates activation of IGF1R and downstream targets in response to both IGF1 and a mechanical stimulus. In addition, integrins potentiate responsiveness of IGF1R to IGF1 and mechanical forces. We demonstrate that integrin-associated kinases, Rous sarcoma oncogene (SRC) and focal adhesion kinase (FAK), display distinct actions on IGF1 signaling; FAK regulates IGF1R activation and its downstream effectors, AKT and ERK, whereas SRC controls signaling downstream of IGF1R. These findings linked to our observation that IGF1 assembles the formation of a heterocomplex between IGF1R and integrin β3 subunit indicate that the regulation of IGF1 signaling by integrins proceeds by direct receptor-receptor interaction as a possible means to translate biomechanical forces into osteoanabolic signals. PMID:26865633

  1. Different Epigenetic Alterations Are Associated with Abnormal IGF2/Igf2 Upregulation in Neural Tube Defects

    PubMed Central

    Bai, Baoling; Zhang, Qin; Liu, Xiaozhen; Miao, Chunyue; Shangguan, Shaofang; Bao, Yihua; Guo, Jin; Wang, Li; Zhang, Ting; Li, Huili

    2014-01-01

    The methylation status of DNA methylation regions (DMRs) of the imprinted gene IGF2/Igf2 is associated with neural tube defects (NTDs), which are caused by a failure of the neural tube to fold and close and are the second-most common birth defect; however, the characterization of the expression level of IGF2/Igf2 in neural tissue from human fetuses affected with NTDs remains elusive. More importantly, whether abnormal chromatin structure also influences IGF2/Igf2 expression in NTDs is unclear. Here, we investigated the transcriptional activity of IGF2/Igf2 in normal and NTD spinal cord tissues, the methylation status of different DMRs, and the chromatin structure of the promoter. Our data indicated that in NTD samples from both human fetuses and retinoic acid (RA)-treated mouse fetuses, the expression level of IGF2/Igf2 was upregulated 6.41-fold and 1.84-fold, respectively, compared to controls. H19 DMR1, but not IGF2 DMR0, was hypermethylated in human NTD samples. In NTD mice, h19 DMR1 was stable, whereas the chromatin structure around the promoter of Igf2 might be loosened, which was displayed by higher H3K4 acetylation and lower H3K27 trimethylation. Therefore, the data revealed that IGF2/Igf2 expression can be ectopically up-regulated by dual epigenetic factors in NTDs. In detail, the upregulation of IGF2/Igf2 is likely controlled by hypermethylation of H19 DMR1 in human NTDs, however, in acute external RA-induced NTD mice it is potentially determined by more open chromatin structure. PMID:25423083

  2. Relative IGF-1 and IGF-2 gene expression in maternal and fetal tissues from diabetic swine

    SciTech Connect

    Wolverton, C.K.; Leaman, D.W.; White, M.E.; Ramsay, T.G. )

    1990-02-26

    Fourteen pregnant, crossbred gilts were utilized in this study. Seven gilts were injected with alloxan (50 mg/kg) at day 75 of gestation to induce diabetes. Gilts underwent caesarean section on day 105 of gestation. Samples were collected from maternal skeletal muscle, adipose tissue, uterus and endometrium; and from fetal skeletal muscle, adipose tissue, placenta, liver, lung, kidney, heart, brain and spleen. Tissues were frozen in liquid nitrogen for later analysis of IGF-1 and IGF-2 gene expression. Samples were pooled and total RNA was isolated using the guanidine isothiocynate method. Total mRNA was analyzed by dot blot hybridization. Blots were probed with {sup 32}P-cDNA for porcine IGF-1 and rat IGF-2. IGF-1 gene expression in maternal tissues was unaffected by diabetes. Maternal diabetes increased IGF-2 mRNA in maternal adipose tissue but exhibited no effect in muscle or uterus. Expression of IGF-2 by maternal endometrium was decreased by diabetes. Maternal diabetes induced an increase in IGF-1 gene expression in muscle and placenta while causing an increase in IGF-2 expression in fetal liver and placenta. IGF-2 mRNA was lower in lung from fetuses of diabetic mothers than in controls. These results suggest that maternal diabetes alters IGF-1 and IGF-2 gene expression in specific tissues and differential regulation of these genes appears to exist in the mother and developing fetus.

  3. Microsatellite polymorphism in the P1 promoter region of the IGF-1 gene is associated with endometrial cancer

    PubMed Central

    KWASNIEWSKI, WOJCIECH; GOZDZICKA-JOZEFIAK, ANNA; WOLUN-CHOLEWA, MARIA; POLAK, GRZEGORZ; SIEROCINSKA-SAWA, JADWIGA; KWASNIEWSKA, ANNA; KOTARSKI, JAN

    2016-01-01

    -20 genotype. The present study suggested that it is rather likely that the polymorphisms in the IGF-1 promoter are associated with EC in Caucasian females with regard to its development. In the present study, polymorphisms of the IGF-1 promoter may have been introduced during the genesis of EC and contributed to it by leading to aberrant expression of IGF-1. PMID:27121258

  4. Bidirectional TSH and IGF-1 Receptor Cross Talk Mediates Stimulation of Hyaluronan Secretion by Graves' Disease Immunoglobins

    PubMed Central

    Krieger, Christine C.; Neumann, Susanne; Place, Robert F.; Marcus-Samuels, Bernice

    2015-01-01

    Context: There is no pathogenetically linked medical therapy for Graves' ophthalmopathy (GO). Lack of animal models and conflicting in vitro studies have hindered the development of such therapy. Recent reports propose that Graves' Igs bind to and activate thyrotropin receptors (TSHRs) and IGF-1 receptors (IGF-1Rs) on cells in orbital fat, stimulating hyaluronan (HA) secretion, a component of GO. Objective: The objective of the study was to investigate potential cross talk between TSHRs and IGF-1Rs in the pathogenesis of GO using a sensitive HA assay. Design/Setting/Participants: Orbital fibroblasts from GO patients were collected in an academic clinical practice and cultured in a research laboratory. Cells were treated with TSH, IGF-1, and a monoclonal Graves' Ig M22. Main Outcome Measures: HA was measured by a modified ELISA. Results: Simultaneous activation by TSH and IGF-1 synergistically increased HA secretion from 320 ± 52 for TSH and 430 ± 65 μg/mL for IGF-1 alone, to 1300 ± 95 μg/mL. IGF-1 shifted the TSH EC50 19-fold to higher potency. The dose response to M22 was biphasic. An IGF-1R antagonist inhibited the higher potency phase but had no effect on the lower potency phase. M22 did not cause IGF-1R autophosphorylation. A TSHR antagonist abolished both phases of M22-stimulated HA secretion. Conclusions: M22 stimulation of HA secretion by GO fibroblasts/preadipocytes involves cross talk between TSHR and IGF-1R. This cross talk relies on TSHR activation rather than direct activation of IGF-1R and leads to synergistic stimulation of HA secretion. These data propose a model for GO pathogenesis that explains previous contradictory results and argues for TSHR as the primary therapeutic target for GO. PMID:25485727

  5. Dephosphorylation of human insulin-like growth factor I (IGF-I) receptors by membrane-associated tyrosine phosphatases.

    PubMed Central

    Peraldi, P; Hauguel-de Mouzon, S; Alengrin, F; Van Obberghen, E

    1992-01-01

    The insulin-like growth factor-I (IGF-I) receptor exhibits structural and functional similarities to the insulin receptor. Although the regulation of the insulin-receptor tyrosine kinase has been extensively investigated, the mechanisms involved in phosphorylation/dephosphorylation of the IGF-I receptor have received only little attention. To obtain a better understanding of the mode of IGF-I action, we have investigated the effects of protein phosphotyrosine phosphatases (PTPases) on the phosphorylation status of the IGF-I receptor. The dephosphorylation of the human IGF-I receptor by membrane-associated tyrosine phosphatases was studied by an immuno-enzymic assay based on the recognition of phosphotyrosine residues by anti-phosphotyrosine antibodies. Using intact IGF-I receptors as substrates, we show that they could be completely dephosphorylated by different cellular PTPases. Three pieces of evidence indicate that receptor dephosphorylation takes place on phosphotyrosine, i.e. the inhibition profile of phosphatase activity by zinc and vanadate, its absolute requirement for thiol compounds and the diminution of [32P]phosphotyrosine labelling of the beta subunit assessed by SDS/PAGE and phosphoamino acid analysis. Tyrosine kinase activity and autophosphorylation of the IGF-I receptor were decreased in a dose-dependent manner by PTPases, indicating that partial dephosphorylation of the receptor was associated with a decrease in its intrinsic activity. The sensitivity of the activated human IGF-I receptor to dephosphorylation on tyrosine leads to the speculation that IGF-I receptor activity might be regulated by mechanisms such as those described for the insulin receptor. Further investigation of the pathways of IGF-I receptor dephosphorylation will contribute to define the role(s) of PTPases in the overall mechanism of IGF-I signalling. Images Fig. 2. Fig. 3. Fig. 4. Fig. 5. PMID:1322128

  6. Humanin: Functional Interfaces with IGF-I.

    PubMed

    Xiao, J; Kim, S-J; Cohen, P; Yen, K

    2016-08-01

    Humanin is the first newly discovered peptide encoded in the mitochondrial genome in over three decades. It is the first member of a novel class of mitochondrial derived peptides. This small, 24 amino acid peptide was initially discovered to have neuroprotective effects and subsequent experiments have shown that it is beneficial in a diverse number of disease models including stroke, cardiovascular disease, and cancer. Over a decade ago, our lab found that humanin bound IGFBP-3 and more recent studies have found it to decrease circulating IGF-I levels. In turn, IGF-I also seems to regulate humanin levels and in this review, we cover the known interaction between humanin and IGF-I. Although the exact mechanism for how humanin and IGF-I regulate each other still needs to be elucidated, it is clear that humanin is a new player in IGF-I signaling. PMID:27082450

  7. Loss of extracellular superoxide dismutase leads to acute lung damage in the presence of ambient air: a potential mechanism underlying adult respiratory distress syndrome.

    PubMed

    Gongora, Maria Carolina; Lob, Heinrich E; Landmesser, Ulf; Guzik, Tomasz J; Martin, W David; Ozumi, Kiyoski; Wall, Susan M; Wilson, David Scott; Murthy, Niren; Gravanis, Michael; Fukai, Tohru; Harrison, David G

    2008-10-01

    The extracellular superoxide dismutase 3 (SOD3) is highly expressed in both blood vessels and lungs. In different models of pulmonary injury, SOD3 is reduced; however, it is unclear whether this contributes to lung injury. To study the role of acute SOD3 reduction in lung injury, the SOD3 gene was deleted in adult mice by using the Cre-Lox technology. Acute reduction of SOD3 led to a fivefold increase in lung superoxide, marked inflammatory cell infiltration, a threefold increase in the arterial-alveolar gradient, respiratory acidosis, histological changes similar to those observed in adult respiratory distress syndrome, and 85% mortality. Treatment with the SOD mimetic MnTBAP and intranasal administration of SOD-containing polyketal microparticles reduced mortality, prevented the histological alterations, and reduced lung superoxide levels. To understand how mice with the SOD3 embryonic deletion survived without lung injury, gene array analysis was performed. These data demonstrated the up-regulation of 37 genes and down-regulation of nine genes, including those involved in cell signaling, inflammation, and gene transcription in SOD3-/- mice compared with either mice with acute SOD3 reduction or wild-type controls. These studies show that SOD3 is essential for survival in the presence of ambient oxygen and that acute loss of this enzyme can lead to severe lung damage. Strategies either to prevent SOD3 inactivation or to augment its levels might prove useful in the treatment of acute lung injury. PMID:18787098

  8. Long R3 insulin-like growth factor-I (IGF-I) infusion stimulates organ growth but reduces plasma IGF-I, IGF-II and IGF binding protein concentrations in the guinea pig.

    PubMed

    Conlon, M A; Tomas, F M; Owens, P C; Wallace, J C; Howarth, G S; Ballard, F J

    1995-08-01

    We have tested whether an animal with substantial amounts of both IGF-I and IGF-II in circulation, such as the guinea pig, would respond to chronic IGF infusion in the same manner as the adult rat, which has negligible amounts of IGF-II in blood. Female guinea pigs of 350 g body weight were continuously infused for 7 days with recombinant guinea pig IGF-I or -II (120 or 360 micrograms/day) or long R3 IGF-I (LR3IGF-I) (120 micrograms/day), an analogue which has much reduced affinities for IGF binding proteins. IGF-I or IGF-II infusion led to substantial increases in plasma IGF-I or IGF-II respectively in comparison with vehicle-infused animals. Nevertheless, body weight gain, feed intake, feed conversion efficiency and carcass composition were not significantly affected by any treatment (significance was deemed to be P < 0.05). Amongst the tissues examined only the fractional weight (g/kg body weight) of the adrenals was increased, and that only by the higher dose (360 micrograms/day) of IGF-I. However, the fractional weight of adrenals, gut, kidneys and spleen were significantly increased by LR3IGF-I, but again overall growth was not stimulated. A possible explanation for the lack of IGF-I effects is that total circulating IGF concentrations were not increased by these treatments. IGF-II significantly raised total IGF concentrations at the higher dose only. Plasma IGF-I was reduced by IGF-II infusion, as was plasma IGF-II by IGF-I infusion.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7561636

  9. The GH/IGF-1 System in Critical Illness

    PubMed Central

    Elijah, Itoro; Branski, Ludwik K.; Finnerty, Celeste F.; Herndon, David N.

    2013-01-01

    The Growth Hormone and Insulin-like Growth Factor-1 axis plays a pivotal role in critical illness, with a derangement leading to profound changes in metabolism. Protein wasting with skeletal muscle loss, delayed wound healing, and impaired recovery of organ systems are some of the most feared consequences. The use of human recombinant Growth Hormone (rhGH) and Insulin-like Growth Factor-1 (IGF-1) - alone and in combination - has been studied extensively in preclinical and clinical trials. This article reviews the current knowlegde and clinical practice of the use of rhGh and IGF-1 in critically ill patients, with a special focus on the trauma and burns patient population. PMID:21925076

  10. Evidence for synergistic action of transthyretin and IGF-I over the IGF-I receptor.

    PubMed

    Vieira, Marta; Leal, Sónia S; Gomes, Cláudio M; Saraiva, Maria João

    2016-04-01

    Transthyretin (TTR) has a neuroprotective role in the central nervous system (CNS) in Alzheimer's disease (AD) and cerebral ischemia. Increased levels of TTR and activated insulin-like growth factor I receptor (IGF-IR) are associated with reduced neurodegeneration in an AD mouse model. In the present study, we found that TTR and IGF-I have a synergistic effect on activation of one of the IGF-IR signaling pathways. Hippocampus of TTR null mice present decreased levels of phosphorylated IGF-IR and Akt when compared with TTR wild type littermate animals. Cell studies reveal the synergistic effect of TTR and IGF-I in promoting IGF-IR signaling even under glutamate induced toxicity. TTR:IGF-IR complexes are identified and a bio-layer interferometry assay demonstrated an interaction between TTR and IGF-IR with a KD ranging from 99 to 744nM. In summary, our results point to a new TTR role through the IGF-I axis, mediated through TTR-IGF-IR interactions. PMID:26804653

  11. Transcriptional regulation of the IGF signaling pathway by amino acids and insulin-like growth factors during myogenesis in Atlantic salmon.

    PubMed

    Bower, Neil I; Johnston, Ian A

    2010-01-01

    The insulin-like growth factor signalling pathway is an important regulator of skeletal muscle growth. We examined the mRNA expression of components of the insulin-like growth factor (IGF) signalling pathway as well as Fibroblast Growth Factor 2 (FGF2) during maturation of myotubes in primary cell cultures isolated from fast myotomal muscle of Atlantic salmon (Salmo salar). The transcriptional regulation of IGFs and IGFBP expression by amino acids and insulin-like growth factors was also investigated. Proliferation of cells was 15% d(-1) at days 2 and 3 of the culture, increasing to 66% d(-1) at day 6. Three clusters of elevated gene expression were observed during the maturation of the culture associated with mono-nucleic cells (IGFBP5.1 and 5.2, IGFBP-6, IGFBP-rP1, IGFBP-2.2 and IGF-II), the initial proliferation phase (IGF-I, IGFBP-4, FGF2 and IGF-IRb) and terminal differentiation and myotube production (IGF2R, IGF-IRa). In cells starved of amino acids and serum for 72 h, IGF-I mRNA decreased 10-fold which was reversed by amino acid replacement. Addition of IGF-I and amino acids to starved cells resulted in an 18-fold increase in IGF-I mRNA indicating synergistic effects and the activation of additional pathway(s) leading to IGF-I production via a positive feedback mechanism. IGF-II, IGFBP-5.1 and IGFBP-5.2 expression was unchanged in starved cells, but increased with amino acid replacement. Synergistic increases in expression of IGFBP5.2 and IGFBP-4, but not IGFBP5.1 were observed with addition of IGF-I, IGF-II or insulin and amino acids to the medium. IGF-I and IGF-II directly stimulated IGFBP-6 expression, but not when amino acids were present. These findings indicate that amino acids alone are sufficient to stimulate myogenesis in myoblasts and that IGF-I production is controlled by both endocrine and paracrine pathways. A model depicting the transcriptional regulation of the IGF pathway in Atlantic salmon muscle following feeding is proposed. PMID:20559434

  12. Comparisons of mRNA expression for insulin-like growth factor (IGF) type 2 receptor (IGF2R) and IGF-1 in small ovarian follicles between cattle selected and not selected for twin ovulations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Both IGF-1 and -2 stimulate ovarian follicular cell proliferation and antral follicle development. Actions of IGF-1 and -2 are mediated through the IGF type 1 receptor, whereas binding of IGF-2 to the IGF2R results in its degradation. Information on the role of IGF2R in regulating bovine follicula...

  13. Insulin-like growth factor I (IGF-I) in a growth-enhanced transgenic (GH-overexpressing) bony fish, the tilapia (Oreochromis niloticus): indication for a higher impact of autocrine/paracrine than of endocrine IGF-I.

    PubMed

    Eppler, Elisabeth; Caelers, Antje; Shved, Natallia; Hwang, Guylin; Rahman, Azizur M; Maclean, Norman; Zapf, Jürgen; Reinecke, Manfred

    2007-08-01

    Several lines of growth hormone (GH)-overexpressing fish have been produced and analysed for growth and fertility parameters. However, only few data are available on the growth-promoting hormone insulin-like growth factor I (IGF-I) that mediates most effects of GH, and these are contradictory. Using quantitative real-time RT-PCR, radioimmunoassay, in situ hybridization, immunohistochemistry, and radiochromatography we investigated IGF-I and IGF binding proteins (IGFBPs) in an adult (17 months old) transgenic (GH-overexpressing) tilapia (Oreochromis niloticus). The transgenics showed an around 1.5-fold increase in length and an approximately 2.3-fold higher weight than the non-transgenics. Using radioimmunoassay, the serum IGF-I levels were lower (6.22 +/- 0.75 ng/ml) in transgenic than in wild-type (15.01 +/- 1.49 ng/ml) individuals (P = 0.0012). Radioimmunoassayable IGF-I in transgenic liver was 4.2-times higher than in wild-type (16.0 +/- 2.21 vs. 3.83 +/- 0.71 ng/g, P = 0.0017). No hepatocytes in wild-type but numerous hepatocytes in transgenic liver contained IGF-I-immunoreactivity. RT-PCR revealed a 1.4-times higher IGF-I mRNA expression in the liver of the transgenics (10.51 +/- 0.82 vs. 7.3 +/- 0.49 pg/microg total RNA, P = 0.0032). In correspondence, in situ hybridization showed more IGF-I mRNA containing hepatocytes in the transgenics. A twofold elevated IGF-I mRNA expression was determined in the skeletal muscle of transgenics (0.33 +/- 0.02 vs. 0.16 +/- 0.01 pg/microg total RNA, P < 0.0001). Both liver and serum of transgenics showed increased IGF-I binding. The increased IGFBP content in the liver may lead to retention of IGF-I, and/or the release of IGF-I into the circulation may be slower resulting in accumulation of IGF-I in the hepatocytes. Our results indicate that the enhanced growth of the transgenics likely is due to enhanced autocrine/paracrine action of IGF-I in extrahepatic sites, as shown here for skeletal muscle. PMID:17431805

  14. Characterization data of gilthead sea bream (Sparus aurata) IGF-I receptors (IGF-IRa/Rb)

    PubMed Central

    Vélez, Emilio J.; Azizi, Sheida; Salmerón, Cristina; Chan, Shu Jin; Nematollahi, Mohammad Ali; Amiri, Bagher Mojazi; Navarro, Isabel; Capilla, Encarnación; Gutiérrez, Joaquim

    2016-01-01

    In this data article we describe the coding sequence of two IGF-IR paralogues (IGF-IRa and IGF-IRb) obtained from gilthead sea bream embryos. The putative protein architecture (domains and other important motifs) was determined and, amino acid sequences alignment and phylogenetic analysis of both receptors together with IGF-IR orthologues from different vertebrates was performed. Additionally, a semi-quantitative conventional PCR was done to analyze the mRNA expression of both receptors in different tissues of gilthead sea bream. These data will assist in further physiological studies in this species. In this sense, the expression of both receptors during ontogeny in muscle as well as the differential effects of IGF-I and IGF-II on their regulation during in vitro myogenesis has been recently studied (doi: 10.1016/j.ygcen.2015.11.011; [1]). PMID:26904713

  15. Characterization data of gilthead sea bream (Sparus aurata) IGF-I receptors (IGF-IRa/Rb).

    PubMed

    Vélez, Emilio J; Azizi, Sheida; Salmerón, Cristina; Chan, Shu Jin; Nematollahi, Mohammad Ali; Amiri, Bagher Mojazi; Navarro, Isabel; Capilla, Encarnación; Gutiérrez, Joaquim

    2016-03-01

    In this data article we describe the coding sequence of two IGF-IR paralogues (IGF-IRa and IGF-IRb) obtained from gilthead sea bream embryos. The putative protein architecture (domains and other important motifs) was determined and, amino acid sequences alignment and phylogenetic analysis of both receptors together with IGF-IR orthologues from different vertebrates was performed. Additionally, a semi-quantitative conventional PCR was done to analyze the mRNA expression of both receptors in different tissues of gilthead sea bream. These data will assist in further physiological studies in this species. In this sense, the expression of both receptors during ontogeny in muscle as well as the differential effects of IGF-I and IGF-II on their regulation during in vitro myogenesis has been recently studied (doi: 10.1016/j.ygcen.2015.11.011; [1]). PMID:26904713

  16. IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis.

    PubMed

    Peixoto Lira, Régia Caroline; Fedatto, Paola Fernanda; Marco Antonio, David Santos; Leal, Letícia Ferro; Martinelli, Carlos Eduardo; de Castro, Margaret; Tucci, Silvio; Neder, Luciano; Ramalho, Leandra; Seidinger, Ana Luiza; Cardinalli, Izilda; Mastellaro, Maria José; Yunes, José Andres; Brandalise, Silvia Regina; Tone, Luiz Gonzaga; Rauber Antonini, Sonir Roberto; Scrideli, Carlos Alberto

    2015-06-01

    Deregulation of the IGF system observed in human tumors indicates a role in malignant cell transformation and in tumor cell proliferation. Although overexpression of the IGF2 and IGF1R genes was described in adrenocortical tumors (ACTs), few studies reported their profiles in pediatric ACTs. In this study, the IGF2 and IGF1R expression was evaluated by RT-qPCR according to the patient's clinical/pathological features in 60 pediatric ACT samples, and IGF1R protein was investigated in 45 samples by immunohistochemistry (IHC). Whole transcriptome and functional assays were conducted after IGF1R inhibition with OSI-906 in NCI-H295A cell line. Significant IGF2 overexpression was found in tumor samples when compared with non-neoplastic samples (P<0.001), significantly higher levels of IGF1R in patients with relapse/metastasis (P=0.031) and moderate/strong IGF1R immunostaining in 62.2% of ACTs, but no other relationship with patient survival and clinical/pathological features was observed. OSI-906 treatment downregulated genes associated with MAPK activity, induced limited reduction of cell viability and increased the apoptosis rate. After 24h, the treatment also decreased the expression of genes related to the steroid biosynthetic process, the protein levels of the steroidogenic acute regulatory protein (STAR), and androgen secretion in cell medium, supporting the role of IGF1R in steroidogenesis of adrenocortical carcinoma cells. Our data showed that the IGF1R overexpression could be indicative of aggressive ACTs in children. However, in vitro treatments with high concentrations of OSI-906 (>1μM) showed limited reduction of cell viability, suggesting that OSI-906 alone could not be a suitable therapy to abolish carcinoma cell growth. PMID:27185872

  17. Circulating IGF1 regulates hippocampal IGF1 levels and brain gene expression during adolescence

    PubMed Central

    Yan, Han; Mitschelen, Matthew; Bixler, Georgina V; Brucklacher, Robert M; Farley, Julie A; Han, Song; Freeman, Willard M; Sonntag, William E

    2012-01-01

    GH and its anabolic mediator, IGF1, are important not only in somatic growth but also in the regulation of brain function. Even though GH treatment has been used clinically to improve body composition and exercise capacity in adults, its influence on central nervous system function has only recently been recognized. This is also the case for children with childhood-onset GH deficiency (GHD) where GH has been used to stimulate bone growth and enhance final adult height. Circulating IGF1 is transported across the blood–brain barrier and IGF1 and its receptors are also synthesized in the brain by neurons and glial and endothelial cells. Nevertheless, the relationship between circulating IGF1 and brain IGF1 remains unclear. This study, using a GH-deficient dwarf rat model and peripheral GH replacement, investigated the effects of circulating IGF1 during adolescence on IGF1 levels in the brain. Our results demonstrated that hippocampal IGF1 protein concentrations during adolescence are highly regulated by circulating IGF1, which were reduced by GHD and restored by systematic GH replacement. Importantly, IGF1 levels in the cerebrospinal fluid were decreased by GHD but not restored by GH replacement. Furthermore, analysis of gene expression using microarrays and RT-PCR indicated that circulating IGF1 levels did not modify the transcription of Igf1 or its receptor in the hippocampus but did regulate genes that are involved in microvascular structure and function, brain development, and synaptic plasticity, which potentially support brain structures involved in cognitive function during this important developmental period. PMID:21750148

  18. Tanshinone IIA Prevents Leu27IGF-II-Induced Cardiomyocyte Hypertrophy Mediated by Estrogen Receptor and Subsequent Akt Activation.

    PubMed

    Weng, Yueh-Shan; Wang, Hsueh-Fang; Pai, Pei-Ying; Jong, Gwo-Ping; Lai, Chao-Hung; Chung, Li-Chin; Hsieh, Dennis Jine-Yuan; HsuanDay, Cecilia; Kuo, Wei-Wen; Huang, Chih-Yang

    2015-01-01

    IGF-IIR plays important roles as a key regulator in myocardial pathological hypertrophy and apoptosis, which subsequently lead to heart failure. Salvia miltiorrhiza Bunge (Danshen) is a traditional Chinese medicinal herb used to treat cardiovascular diseases. Tanshinone IIA is an active compound in Danshen and is structurally similar to 17[Formula: see text]-estradiol (E[Formula: see text]. However, whether tanshinone IIA improves cardiomyocyte survival in pathological hypertrophy through estrogen receptor (ER) regulation remains unclear. This study investigates the role of ER signaling in mediating the protective effects of tanshinone IIA on IGF-IIR-induced myocardial hypertrophy. Leu27IGF-II (IGF-II analog) was shown in this study to specifically activate IGF-IIR expression and ICI 182,780 (ICI), an ER antagonist used to investigate tanshinone IIA estrogenic activity. We demonstrated that tanshinone IIA significantly enhanced Akt phosphorylation through ER activation to inhibit Leu27IGF-II-induced calcineurin expression and subsequent NFATc3 nuclear translocation to suppress myocardial hypertrophy. Tanshinone IIA reduced the cell size and suppressed ANP and BNP, inhibiting antihypertrophic effects induced by Leu27IGF-II. The cardioprotective properties of tanshinone IIA that inhibit Leu27IGF-II-induced cell hypertrophy and promote cell survival were reversed by ICI. Furthermore, ICI significantly reduced phospho-Akt, Ly294002 (PI3K inhibitor), and PI3K siRNA significantly reduced the tanshinone IIA-induced protective effect. The above results suggest that tanshinone IIA inhibited cardiomyocyte hypertrophy, which was mediated through ER, by activating the PI3K/Akt pathway and inhibiting Leu27IGF-II-induced calcineurin and NFATC3. Tanshinone IIA exerted strong estrogenic activity and therefore represented a novel selective ER modulator that inhibits IGF-IIR signaling to block cardiac hypertrophy. PMID:26621443

  19. Regulation of Human Trophoblast GLUT1 Glucose Transporter by Insulin-Like Growth Factor I (IGF-I)

    PubMed Central

    Baumann, Marc U.; Schneider, Henning; Malek, Antoine; Palta, Vidya; Surbek, Daniel V.; Sager, Ruth; Zamudio, Stacy; Illsley, Nicholas P.

    2014-01-01

    Glucose transport to the fetus across the placenta takes place via glucose transporters in the opposing faces of the barrier layer, the microvillous and basal membranes of the syncytiotrophoblast. While basal membrane content of the GLUT1 glucose transporter appears to be the rate-limiting step in transplacental transport, the factors regulating transporter expression and activity are largely unknown. In view of the many studies showing an association between IGF-I and fetal growth, we investigated the effects of IGF-I on placental glucose transport and GLUT1 transporter expression. Treatment of BeWo choriocarcinoma cells with IGF-I increased cellular GLUT1 protein. There was increased basolateral (but not microvillous) uptake of glucose and increased transepithelial transport of glucose across the BeWo monolayer. Primary syncytial cells treated with IGF-I also demonstrated an increase in GLUT1 protein. Term placental explants treated with IGF-I showed an increase in syncytial basal membrane GLUT1 but microvillous membrane GLUT1 was not affected. The placental dual perfusion model was used to assess the effects of fetally perfused IGF-I on transplacental glucose transport and syncytial GLUT1 content. In control perfusions there was a decrease in transplacental glucose transport over the course of the perfusion, whereas in tissues perfused with IGF-I through the fetal circulation there was no change. Syncytial basal membranes from IGF-I perfused tissues showed an increase in GLUT1 content. These results demonstrate that IGF-I, whether acting via microvillous or basal membrane receptors, increases the basal membrane content of GLUT1 and up-regulates basal membrane transport of glucose, leading to increased transepithelial glucose transport. These observations provide a partial explanation for the mechanism by which IGF-I controls nutrient supply in the regulation of fetal growth. PMID:25157747

  20. Insulin-like growth factor I (IGF-I) and its receptor (IGF-1R) in the rat anterior pituitary.

    PubMed

    Eppler, Elisabeth; Jevdjovic, Tanja; Maake, Caroline; Reinecke, Manfred

    2007-01-01

    Few and controversial results exist on the cellular sites of insulin-like growth factor (IGF)-I synthesis and the type 1 IGF receptor (IGF-1R) in mammalian anterior pituitary. Thus, the present study analysed IGF-I and the IGF-1R in rat pituitary. Reverse transcription-polymerase chain reaction revealed IGF-I and IGF-1R mRNA expression in pituitary. The sequences of both were identical to the corresponding sequences in other rat organs. In situ hybridization localized IGF-I mRNA in endocrine cells. The majority of the growth hormone (GH) cells and numerous adrenocorticotropic hormone (ACTH) cells exhibited IGF-1R-immunoreactivity at the cell membrane. At lower densities, IGF-1 receptors were also present at the other hormone-producing cell types, indicating a physiological impact of IGF-I for all endocrine cells. IGF-I-immunoreactivity was located constantly in almost all ACTH-immunoreactive cells. At the ultrastructural level, IGF-I-immunoreactivity was confined to secretory granules in co-existence with ACTH-immunoreactivity, indicating a concomitant release of both hormones. Occasionally, IGF-I-immunoreactivity was detected in an interindividually varying number of GH cells. In some individuals, weak IGF-I-immunoreactions were also detected also in follicle-stimulating hormone and luteinizing hormone cells. Thus, IGF-I seems to be produced as a constituent in ACTH cells, possibly indicating its particular importance in stress response. Generally, IGF-I from the endocrine cells may regulate synthesis and/or release of hormones in an autocrine/paracrine manner as well as prevent apoptosis and stimulate proliferation. Production of IGF-I in GH cells may depend on the physiological status, most likely the serum IGF-I level. IGF-I released from GH cells may suppress GH synthesis and/or release by an autocrine feedback mechanism in addition to the endocrine route. PMID:17241280

  1. PAPP-A and the IGF system.

    PubMed

    Monget, Philippe; Oxvig, Claus

    2016-06-01

    Firstly discovered as a placental protein present abundantly in the circulation of pregnant women, pregnancy-associated plasma protein-A (PAPP-A) is widely expressed in multiple tissues. PAPP-A is a metalloproteinase that is able to specifically cleave three insulin-like growth factor binding proteins (IGFBPs): IGFBP-2, -4 and -5. PAPP-A binds tightly to glycosaminoglycans present on the surface of cells, thus functioning within tissues as a growth-promoting enzyme, releasing bioactive IGF in close proximity to the IGF receptor. Pro-MBP and stanniocalcin-2 (STC2) appear to be the main inhibitors of PAPP-A activity, by forming a covalent complex with the protease. According to in vivo experiments, IGFBP-4 is believed to be the main PAPP-A substrate to regulate IGF bioavailability. The regulation of PAPP-A includes transcriptional control of its gene, competing reactions with other IGFBPs potentially sequestering IGF from IGFBP-4 and hence antagonizing PAPP-A-mediated IGF activation, and proteolytic inhibition of PAPP-A. Finally, PAPP-A may serve as a therapeutic target to indirectly inhibit IGF signalling in tissues where this is driven by increased PAPP-A activity. By taking advantage of the intricate interaction between PAPP-A and IGFBP-4, highly specific and selective inhibition of PAPP-A is possible. PMID:27155776

  2. Serum IGF1, IGF2 and IGFBP3 and risk of advanced colorectal adenoma.

    PubMed

    Gao, Ying; Katki, Hormuzd; Graubard, Barry; Pollak, Michael; Martin, Michael; Tao, Yuzhen; Schoen, Robert E; Church, Timothy; Hayes, Richard B; Greene, Mark H; Berndt, Sonja I

    2012-07-15

    The insulin-like growth factor (IGF) signaling pathway is involved in cell proliferation and differentiation. Elevated serum IGF1 levels have been associated with increased colorectal cancer risk; however, studies of this association with colorectal adenoma are inconclusive. We examined serum IGF1, IGF2 and IGFBP3 levels in relation to risk of advanced colorectal adenoma in a case-control study within the prostate, lung, colorectal and ovarian cancer screening trial. A total of 764 advanced, left-sided colorectal adenoma cases and 775 controls frequency-matched on gender and ethnicity, without evidence of a left-sided polyp on sigmoidoscopy were included in the current study. Serum levels of IGF1, IGF2 and IGFBP3 were measured using an enzyme linked immunosorbent assay in serum samples collected at baseline. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the associations adjusting for age, race, sex, year of blood draw, body mass index, smoking and education. Higher IGF1 levels were associated with increased adenoma risk: ORs = 1.58 (95% CI = 1.16-2.16), 1.42 (95% CI = 1.04-1.93), and 1.80 (95% CI = 1.30-2.47) for the second, third and fourth quartiles, respectively (p(trend) = 0.002). Elevated IGF2 levels were also associated with increased adenoma risk (OR = 1.43, 95% CI = 1.05-1.96 for the fourth vs. first quartile, p(trend) = 0.02), but the association was no longer significant after adjustment for IGF1 (p(trend) = 0.28). IGFBP3 levels were not associated with adenoma risk. Our analysis showed a significant positive association between circulating IGF1 levels and risk of advanced colorectal adenoma, suggesting that IGF1 is associated with the pivotal precursor to colorectal cancer. PMID:21932422

  3. Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation.

    PubMed

    Grønskov, Karen; Poole, Rebecca L; Hahnemann, Johanne M D; Thomson, Jennifer; Tümer, Zeynep; Brøndum-Nielsen, Karen; Murphy, Rinki; Ravn, Kirstine; Melchior, Linea; Dedic, Alma; Dolmer, Birgitte; Temple, I Karen; Boonen, Susanne E; Mackay, Deborah J G

    2011-05-01

    Silver-Russell syndrome (SRS) is characterised by prenatal and postnatal growth retardation, dysmorphic facial features, and body asymmetry. In 35-60% of SRS cases the paternally methylated imprinting control region (ICR) upstream of the H19 gene (H19-ICR) is hypomethylated, leading to downregulation of IGF2 and bi-allelic expression of H19. H19 and IGF2 are reciprocally imprinted genes on chromosome 11p15. The expression is regulated by the imprinted methylation of the ICR, which modulates the transcription of H19 and IGF2 facilitated by enhancers downstream of H19. A promoter element of IGF2, IGF2P0, is differentially methylated equivalently to the H19-ICR, though in a small number of SRS cases this association is disrupted--that is, hypomethylation affects either H19-ICR or IGF2P0. Three pedigrees associated with hypomethylation of IGF2P0 in the probands are presented here, two with paternally derived deletions, and one with a balanced translocation of inferred paternal origin. They all have a breakpoint within the H19/IGF2 enhancer region. One proband has severe growth retardation, the others have SRS. This is the first report of paternally derived structural chromosomal mutations in 11p15 causing SRS. These cases define a novel aetiology of the growth retardation in SRS, namely, dissociation of IGF2 from its enhancers. PMID:21278389

  4. Effects of fasting on IGF-I, IGF-II, and IGF-binding protein mRNA concentrations in channel catfish (Ictalurus punctatus)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effects of fasting on IGF-I, IGF-II, and IGF-binding proteins (IGFBPs) in channel catfish were examined. Fed control fish (Fed) were compared to fish that had been fasted for 30 days followed by 15 days of additional feeding (Restricted). Sequence alignment and similarity to orthologous protei...

  5. Na+ transport across rumen epithelium of hay-fed sheep is acutely stimulated by the peptide IGF-1 in vitro.

    PubMed

    Shen, Zanming; Martens, Holger; Schweigel-Röntgen, Monika

    2012-04-01

    An energy-rich diet leads to enhanced ruminal Na(+) absorption, which is associated with elevated plasma insulin-like growth factor 1 (IGF-1) levels and an increased number of IGF-1 receptors in rumen papillae. This study examined the in vitro effect of IGF-1 on Na(+) transport across the rumen epithelium of hay-fed sheep, in which the IGF-1 concentration in plasma is lower than in concentrate-fed animals. At concentrations ranging from 20 to 100 μg l(-1), serosal LR3-IGF-1, a recombinant analogue of IGF-1, rapidly (within 30 min) stimulated the mucosal-to-serosal Na(+) flux (J(ms)Na) and consequently the net Na(+) flux (J(net)Na). Compared with controls, J(net)Na increased by about 60% (P < 0.05) following the serosal application of LR3-IGF-1 (20 μg l(-1)). The IGF-1-induced increment of J(ms)Na and J(net)Na was inhibited by mucosal amiloride (1 mmol l(-1)). Neither IGF-1 nor amiloride altered tissue conductance or the short-circuit current of the isolated rumen epithelium. These data support the assumption that the stimulating effect of serosally applied IGF-1 on Na(+) transport across the rumen epithelium is mediated by Na(+)-H(+) exchange (NHE). A further study was performed with cultured rumen epithelial cells and a fluorescent probe (BCECF) to estimate the rate of pH(i) recovery after acid loading. The pH(i) of isolated rumen epithelial cells was 6.43 ± 0.15 after butyrate loading and recovered by 0.26 ± 0.02 pH units (15 min)(-1). Application of LR3-IGF-1 (20 μg l(-1)) significantly increased the rate of pH(i) recovery to 0.33 ± 0.02 pH units (15 min)(-1). Amiloride administration reduced the recovery rate in both control and IGF-1-stimulated cells. These results show, for the first time, that an acute effect of IGF-1 on Na(+) absorption across rumen epithelium results from increased NHE activity. Insulin-like growth factor 1 is thus important for the fast functional adaptation of ruminal Na(+) transport via NHE. PMID:22227200

  6. Improving expression of recombinant human IGF-1 using IGF-1R knockout CHO cell lines.

    PubMed

    Romand, Sandrine; Jostock, Thomas; Fornaro, Mara; Schmidt, Joerg; Ritter, Anett; Wilms, Burkhard; Laux, Holger

    2016-05-01

    Chinese Hamster Ovary (CHO) cells are widely used for the large-scale production of recombinant biopharmaceuticals. However, attempts to express IGF-1 (a mutated human Insulin-like growth factor 1 Ea peptide (hIGF-1Ea mut)) in CHO cells resulted in poor cell growth and low productivity (0.1-0.2 g/L). Human IGF-1 variants negatively impacted CHO cell growth via the IGF-1 receptor (IGF-1R). Therefore knockout (KO) of the IGF-1R gene in two different CHO cell lines as well as knockdown (KD) of IGF-1R in one CHO cell line were performed. These cell line engineering approaches decreased significantly the hIGF-1 mediated cell growth inhibition and increased productivity of both KO CHO cell lines as well as of the KD CHO cell line. A productivity increase of 10-fold at pool level and sevenfold at clone level was achieved, resulting in a titer of 1.3 g/L. This data illustrate that cell line engineering approaches are powerful tools to improve the yields of recombinant proteins which are difficult to produce in CHO cells. Biotechnol. Bioeng. 2016;113: 1094-1101. © 2015 Wiley Periodicals, Inc. PMID:26523469

  7. Serum insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 levels in severe iodine deficiency.

    PubMed

    Alikaşifoğlu, Ayfer; Ozön, Alev; Yordam, Nurşen

    2002-01-01

    Iodine deficiency is an important public health problem worldwide. It is well known that it has severe consequences such as brain damage, developmental delay, deficits in hearing and learning and lower intellectual attainment. It also has a negative impact on growth. In this study, we aimed to address this issue and we assessed height standard deviation scores of children living in an area of severe iodine deficiency in comparison to those living in a mild iodine deficiency area. Serum levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), thyroxine (T4), and thyroid stimulating hormone (TSH) were also analyzed to investigate the mechanisms by which iodine depletion leads to growth failure. Pubertal children in a severe iodine deficient SID area had lower height standard deviation scores (HSDS), IGF-I and IGFBP-3 levels than those living in mild iodine deficient MID area. Similar findings could not be elucidated in the prepubertal age group. The major determinants of HSDS were age, IGF-I, IGFBP-3 and TSH. IGF-I and IGFBP-3 were negatively correlated with T4. These findings suggest that iodine deficiency has a negative impact on growth, as well as IGF-I and IGFBP-3 levels. This effect seems to be due to the derangements in thyroid hormone economy arising from iodine depletion. The degree of this impact may be related to the duration of iodine depletion or may be dependent on the developmental stage of the organism at the time of iodine depletion. PMID:12405432

  8. How IGF-1 activates its receptor

    PubMed Central

    Kavran, Jennifer M; McCabe, Jacqueline M; Byrne, Patrick O; Connacher, Mary Katherine; Wang, Zhihong; Ramek, Alexander; Sarabipour, Sarvenaz; Shan, Yibing; Shaw, David E; Hristova, Kalina; Cole, Philip A; Leahy, Daniel J

    2014-01-01

    The type I insulin-like growth factor receptor (IGF1R) is involved in growth and survival of normal and neoplastic cells. A ligand-dependent conformational change is thought to regulate IGF1R activity, but the nature of this change is unclear. We point out an underappreciated dimer in the crystal structure of the related Insulin Receptor (IR) with Insulin bound that allows direct comparison with unliganded IR and suggests a mechanism by which ligand regulates IR/IGF1R activity. We test this mechanism in a series of biochemical and biophysical assays and find the IGF1R ectodomain maintains an autoinhibited state in which the TMs are held apart. Ligand binding releases this constraint, allowing TM association and unleashing an intrinsic propensity of the intracellular regions to autophosphorylate. Enzymatic studies of full-length and kinase-containing fragments show phosphorylated IGF1R is fully active independent of ligand and the extracellular-TM regions. The key step triggered by ligand binding is thus autophosphorylation. DOI: http://dx.doi.org/10.7554/eLife.03772.001 PMID:25255214

  9. The insulin-like growth factor (IGF) axis as an anticancer target in prostate cancer.

    PubMed

    Heidegger, Isabel; Massoner, Petra; Sampson, Natalie; Klocker, Helmut

    2015-10-28

    Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer death in males. In recent years, several new targeting agents have been introduced for the treatment of advanced stages of the disease. However, development of resistance limits the efficacy of new drugs and there is a further need to develop additional novel treatment approaches. One of the most investigated targets in cancer research is the insulin-like growth factor (IGF) axis, whose receptors are overexpressed in several cancer entities including PCa. In preclinical studies in PCa, targeting of the IGF axis receptors showed promising anti-tumor effects. Currently available data on clinical studies do not meet the expectations for this new treatment approach. In this review we provide a summary of preclinical and clinical studies on the IGF axis in PCa including treatment with monoclonal antibodies and tyrosine kinase inhibitors. Moreover, we summarize preliminary results from ongoing studies and discuss limitations and side effects of the substances used. We also address the role of the IGF axis in the biomarkers setting including IGF-binding proteins and genetic variants. PMID:26231734

  10. Insulin-like growth factor 1 (IGF-1) therapy: Mitochondrial dysfunction and diseases.

    PubMed

    Sádaba, M C; Martín-Estal, I; Puche, J E; Castilla-Cortázar, I

    2016-07-01

    This review resumes the association between mitochondrial function and diseases, especially neurodegenerative diseases. Additionally, it summarizes the major role of IGF-1 as a mitochondrial protector, as studied in several experimental models (cirrhosis, aging …). The contribution of mitochondrial dysfunction to impairments in insulin metabolic signaling is also suggested by gene array analysis showing that reductions in gene expression, that regulates mitochondrial ATP production, are associated with insulin resistance and type 2 diabetes mellitus. Moreover, reductions in oxidative capacity of mitochondrial electron transport chain are manifested in obese, insulin-resistant and diabetic patients. Genetic and environmental factors, oxidative stress, and alterations in mitochondrial biogenesis can adversely affect mitochondrial function, leading to insulin resistance and several pathological conditions, such as type 2 diabetes. Finally, it remains essential to know the exact mechanisms involved in mitochondrial generation and metabolism, mitophagy, apoptosis, and oxidative stress to establish new targets in order to develop potentially effective therapies. One of the newest targets to recover mitochondrial dysfunction could be the administration of IGF-1 at low doses. In the last years, it has been observed that IGF-1 therapy has several beneficial effects: restores physiological IGF-1 levels; improves insulin resistance and lipid metabolism; exerts mitochondrial protection; and has hepatoprotective, neuroprotective, antioxidant and antifibrogenic effects. In consequence, treatment of mitochondrial dysfunctions with low doses of IGF-1 could be a powerful and useful effective therapy to restore normal mitochondrial functions. PMID:27020404

  11. The effects of thyroid hormone on insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) expression in the neonatal rat: prolonged high expression of IGFBP-2 in methimazole-induced congenital hypothyroidism.

    PubMed

    Näntö-Salonen, K; Glasscock, G F; Rosenfeld, R G

    1991-11-01

    In the rat a developmental switch in the serum insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) profile takes place during the first 3 postnatal weeks. The fetal expression pattern of high IGF-II and IGFBP-2 is replaced by the adult pattern of low levels of IGF-II and IGFBP-2 and high levels of IGF-I and IGFBP-3. The regulatory mechanisms mediating these changes are unknown, but may include perinatal changes in endocrine function. To study the effects of thyroid function and the perinatal thyroid secretory burst on IGF and IGFBP expression, we established a rat model of congenital hypothyroidism, leading to marked postnatal growth retardation during the perinatal period. The hypothyroid animals lacked the steep rise in serum IGF-I levels normally occurring during the third week of life, showing only a modest rise to approximately 50% of control levels. The pattern of serum IGF-II decline in hypothyroid animals was slightly different from that in controls, with lower IGF-II levels during the second week of life and a slower decline down to the very low final levels. The hypothyroid pups continued to express high levels of IGFBP-2 up to the age of 19 days, while the control animals, after a slow initial decline, showed an abrupt fall of IGFBP-2 serum levels during the third week of life. Liver IGFBP-2 mRNA levels reflected the serum changes, with elevated IGFBP-2 mRNA in hypothyroid animals. The expression of other IGFBPs did not differ from that in the control group. At the age of 18 days, serum GH levels in the hypothyroid animals were approximately one third of control GH levels, which suggests a role for GH as a possible mediator of thyroid hormone actions on the IGF system. The changes in growth parameters and in the IGF and IGFBP profile of hypothyroid pups could be abolished by thyroid hormone replacement from birth. We conclude that thyroid hormone is, directly or indirectly, essential for some of the neonatal changes in IGF and IGFBP profiles

  12. Paternally Inherited IGF2 Mutation and Growth Restriction.

    PubMed

    Begemann, Matthias; Zirn, Birgit; Santen, Gijs; Wirthgen, Elisa; Soellner, Lukas; Büttel, Hans-Martin; Schweizer, Roland; van Workum, Wilbert; Binder, Gerhard; Eggermann, Thomas

    2015-07-23

    In humans, mutations in IGF1 or IGF1R cause intrauterine and postnatal growth restriction; however, data on mutations in IGF2, encoding insulin-like growth factor (IGF) II, are lacking. We report an IGF2 variant (c.191C→A, p.Ser64Ter) with evidence of pathogenicity in a multigenerational family with four members who have growth restriction. The phenotype affects only family members who have inherited the variant through paternal transmission, a finding that is consistent with the maternal imprinting status of IGF2. The severe growth restriction in affected family members suggests that IGF-II affects postnatal growth in addition to prenatal growth. Furthermore, the dysmorphic features of affected family members are consistent with a role of deficient IGF-II levels in the cause of the Silver-Russell syndrome. (Funded by Bundesministerium für Bildung und Forschung and the European Union.). PMID:26154720

  13. IGF-1 (Insulin-Like Growth Factor -1) Test

    MedlinePlus

    ... instead of, surgery to try to decrease GH production and return IGF-1 to a normal or ... regular intervals for years afterward to monitor GH production and to detect tumor recurrence. IGF-1 levels ...

  14. Antagonists of IGF:Vitronectin Interactions Inhibit IGF-I-Induced Breast Cancer Cell Functions.

    PubMed

    Kashyap, Abhishek S; Shooter, Gary K; Shokoohmand, Ali; McGovern, Jacqui; Sivaramakrishnan, Manaswini; Croll, Tristan I; Cane, Gaëlle; Leavesley, David I; Söderberg, Ola; Upton, Zee; Hollier, Brett G

    2016-07-01

    We provide proof-of-concept evidence for a new class of therapeutics that target growth factor:extracellular matrix (GF:ECM) interactions for the management of breast cancer. Insulin-like growth factor-I (IGF-I) forms multiprotein complexes with IGF-binding proteins (IGFBP) and the ECM protein vitronectin (VN), and stimulates the survival, migration and invasion of breast cancer cells. For the first time we provide physical evidence for IGFBP-3:VN interactions in breast cancer patient tissues; these interactions were predominantly localized to tumor cell clusters and in stroma surrounding tumor cells. We show that disruption of IGF-I:IGFBP:VN complexes with L(27)-IGF-II inhibits IGF-I:IGFBP:VN-stimulated breast cancer cell migration and proliferation in two- and three-dimensional assay systems. Peptide arrays screened to identify regions critical for the IGFBP-3/-5:VN and IGF-II:VN interactions demonstrated IGFBP-3/-5 and IGF-II binds VN through the hemopexin-2 domain, and VN binds IGFBP-3 at residues not involved in the binding of IGF-I to IGFBP-3. IGFBP-interacting VN peptides identified from these peptide arrays disrupted the IGF-I:IGFBP:VN complex, impeded the growth of primary tumor-like spheroids and, more importantly, inhibited the invasion of metastatic breast cancer cells in 3D assay systems. These studies provide first-in-field evidence for the utility of small peptides in antagonizing GF:ECM-mediated biologic functions and present data demonstrating the potential of these peptide antagonists as novel therapeutics. Mol Cancer Ther; 15(7); 1602-13. ©2016 AACR. PMID:27196774

  15. IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction

    PubMed Central

    Tejada, Thor; Tan, Lin; Torres, Rebecca A.; Calvert, John W.; Lambert, Jonathan P.; Zaidi, Madiha; Husain, Murtaza; Berce, Maria D.; Naib, Hussain; Pejler, Gunnar; Abrink, Magnus; Graham, Robert M.; Lefer, David J.; Naqvi, Nawazish; Husain, Ahsan

    2016-01-01

    Heart disease is a leading cause of death in adults. Here, we show that a few days after coronary artery ligation and reperfusion, the ischemia-injured heart elaborates the cardioprotective polypeptide, insulin-like growth factor-1 (IGF-1), which activates IGF-1 receptor prosurvival signaling and improves cardiac left ventricular systolic function. However, this signaling is antagonized by the chymase, mouse mast cell protease 4 (MMCP-4), which degrades IGF-1. We found that deletion of the gene encoding MMCP-4 (Mcpt4), markedly reduced late, but not early, infarct size by suppressing IGF-1 degradation and, consequently, diminished cardiac dysfunction and adverse structural remodeling. Our findings represent the first demonstration to our knowledge of tissue IGF-1 regulation through proteolytic degradation and suggest that chymase inhibition may be a viable therapeutic approach to enhance late cardioprotection in postischemic heart disease. PMID:27274047

  16. Insulin and insulin-like growth factors (IGFs) stimulate production of IGF-binding proteins by ovarian granulosa cells.

    PubMed

    Grimes, R W; Hammond, J M

    1992-08-01

    Ligand blot analysis of granulosa cell (GC)-conditioned culture medium revealed several easily measurable insulin-like growth factor (IGF)-binding proteins (IGFBPs), including IGFBP-3 [40-44 kilodaltons (kDa)] and IGFBP-2 (34 kDa). In the present study, IGF-I, in a dose-dependent manner, significantly stimulated the production of these IGFBPs. Insulin, but not IGF-II, mimicked IGF-I's action on IGFBP-3 and -2 production, but was less potent. The synthetic IGF, long R3-IGF-I, which has very low affinity for IGFBPs and only slightly reduced affinity for the IGF-I (type I) receptor, had significantly greater potency in stimulating IGFBP-3 and -2 production compared to IGF-I. Des-(1-3)-IGF-I had similar effects. IGF-I, IGF-II, and the IGF-I analogs, but not insulin, also induced production of an unidentified 30-kDa IGFBP not normally detectable in these cultures. However, in the presence of epidermal growth factor (which was without independent effect on the 30-kDa IGFBP), insulin also induced this 30-kDa IGFBP. By Northern analysis the expression of IGFBP-3 mRNA was found to be significantly stimulated by IGF-I. In summary, insulin stimulated IGFBP-3 and -2 production in a manner that mimics that of IGF-I and the more potent long R3-IGF-I. However, its low potency suggested that IGFBP production is regulated via the IGF-I (type I) receptor. The much higher potency of long R3-IGF-I compared to that of IGF-I suggests that the IGFBPs themselves modulate the action of IGFs by sequestering exogenous IGFs. Thus, one cellular response to IGF stimulation is the production of IGFBPs, which, in turn, reduce or negate the biological activity of the IGFs. The effects of insulin-like peptides are exerted at least in part by increasing levels of mRNA for specific BPs. PMID:1379161

  17. Reductions in serum IGF-1 during aging impair health span

    PubMed Central

    Gong, Zhenwei; Kennedy, Oran; Sun, Hui; Wu, YingJie; Williams, Garry A; Klein, Laura; Cardoso, Luis; Matheny, Ronald W; Hubbard, Gene B; Ikeno, Yuji; Farrar, Roger P; Schaffler, Mitchell B; Adamo, Martin L; Muzumdar, Radhika H; Yakar, Shoshana

    2014-01-01

    In lower or simple species, such as worms and flies, disruption of the insulin-like growth factor (IGF)-1 and the insulin signaling pathways has been shown to increase lifespan. In rodents, however, growth hormone (GH) regulates IGF-1 levels in serum and tissues and can modulate lifespan via/or independent of IGF-1. Rodent models, where the GH/IGF-1 axis was ablated congenitally, show increased lifespan. However, in contrast to rodents where serum IGF-1 levels are high throughout life, in humans, serum IGF-1 peaks during puberty and declines thereafter during aging. Thus, animal models with congenital disruption of the GH/IGF-1 axis are unable to clearly distinguish between developmental and age-related effects of GH/IGF-1 on health. To overcome this caveat, we developed an inducible liver IGF-1-deficient (iLID) mouse that allows temporal control of serum IGF-1. Deletion of liver Igf -1 gene at one year of age reduced serum IGF-1 by 70% and dramatically impaired health span of the iLID mice. Reductions in serum IGF-1 were coupled with increased GH levels and increased basal STAT5B phosphorylation in livers of iLID mice. These changes were associated with increased liver weight, increased liver inflammation, increased oxidative stress in liver and muscle, and increased incidence of hepatic tumors. Lastly, despite elevations in serum GH, low levels of serum IGF-1 from 1 year of age compromised skeletal integrity and accelerated bone loss. We conclude that an intact GH/IGF-1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology. PMID:24341939

  18. Reductions in serum IGF-1 during aging impair health span.

    PubMed

    Gong, Zhenwei; Kennedy, Oran; Sun, Hui; Wu, YingJie; Williams, Garry A; Klein, Laura; Cardoso, Luis; Matheny, Ronald W; Hubbard, Gene B; Ikeno, Yuji; Farrar, Roger P; Schaffler, Mitchell B; Adamo, Martin L; Muzumdar, Radhika H; Yakar, Shoshana

    2014-06-01

    In lower or simple species, such as worms and flies, disruption of the insulin-like growth factor (IGF)-1 and the insulin signaling pathways has been shown to increase lifespan. In rodents, however, growth hormone (GH) regulates IGF-1 levels in serum and tissues and can modulate lifespan via/or independent of IGF-1. Rodent models, where the GH/IGF-1 axis was ablated congenitally, show increased lifespan. However, in contrast to rodents where serum IGF-1 levels are high throughout life, in humans, serum IGF-1 peaks during puberty and declines thereafter during aging. Thus, animal models with congenital disruption of the GH/IGF-1 axis are unable to clearly distinguish between developmental and age-related effects of GH/IGF-1 on health. To overcome this caveat, we developed an inducible liver IGF-1-deficient (iLID) mouse that allows temporal control of serum IGF-1. Deletion of liver Igf-1 gene at one year of age reduced serum IGF-1 by 70% and dramatically impaired health span of the iLID mice. Reductions in serum IGF-1 were coupled with increased GH levels and increased basal STAT5B phosphorylation in livers of iLID mice. These changes were associated with increased liver weight, increased liver inflammation, increased oxidative stress in liver and muscle, and increased incidence of hepatic tumors. Lastly, despite elevations in serum GH, low levels of serum IGF-1 from 1 year of age compromised skeletal integrity and accelerated bone loss. We conclude that an intact GH/IGF-1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology. PMID:24341939

  19. Growth hormone, IGF-I and insulin and their abuse in sport

    PubMed Central

    Holt, R I G; Sönksen, P H

    2008-01-01

    There is widespread anecdotal evidence that growth hormone (GH) is used by athletes for its anabolic and lipolytic properties. Although there is little evidence that GH improves performance in young healthy adults, randomized controlled studies carried out so far are inadequately designed to demonstrate this, not least because GH is often abused in combination with anabolic steroids and insulin. Some of the anabolic actions of GH are mediated through the generation of insulin-like growth factor-I (IGF-I), and it is believed that this is also being abused. Athletes are exposing themselves to potential harm by self-administering large doses of GH, IGF-I and insulin. The effects of excess GH are exemplified by acromegaly. IGF-I may mediate and cause some of these changes, but in addition, IGF-I may lead to profound hypoglycaemia, as indeed can insulin. Although GH is on the World Anti-doping Agency list of banned substances, the detection of abuse with GH is challenging. Two approaches have been developed to detect GH abuse. The first is based on an assessment of the effect of exogenous recombinant human GH on pituitary GH isoforms and the second is based on the measurement of markers of GH action. As a result, GH abuse can be detected with reasonable sensitivity and specificity. Testing for IGF-I and insulin is in its infancy, but the measurement of markers of GH action may also detect IGF-I usage, while urine mass spectroscopy has begun to identify the use of insulin analogues. PMID:18376417

  20. Oncofetal protein IGF2BP3 facilitates the activity of proto-oncogene protein eIF4E through the destabilization of EIF4E-BP2 mRNA.

    PubMed

    Mizutani, R; Imamachi, N; Suzuki, Y; Yoshida, H; Tochigi, N; Oonishi, T; Suzuki, Y; Akimitsu, N

    2016-07-01

    RNA-binding proteins (RBPs) have important roles in tumorigenesis. Although IGF2BP3, an evolutionally conserved RBP, has been reported as a useful diagnostic marker for various cancers and has been considered a regulator of tumorigenesis, little is known of the function of IGF2BP3 because of lack of information regarding IGF2BP3 target mRNAs. Here, we report the identification of IGF2BP3 target mRNAs and IGF2BP3 function in cancer proliferation. We identified mRNAs with altered expression in IGF2BP3-depleted cells by massive sequencing analysis and IGF2BP3-binding RNAs by immunoprecipitation of IGF2BP3 followed by massive sequencing analysis, resulting in the identification of 110 candidates that are negatively regulated by IGF2BP3. We found that IGF2BP3 destabilized EIF4E-BP2 and MEIS3 mRNAs. Co-immunoprecipitation analysis revealed the interaction between IGF2BP3 and ribonucleases such as XRN2 and exosome component. The retarded proliferation of IGF2BP3-depleted cells was partially rescued by the depletion of EIF4E-BP2, which negatively regulates eukaryotic translation initiation factor 4E (eIF4E), an activator of translation and a well-known proto-oncogene. Consistent with this observation, IGF2BP3 depletion reduced phosphorylated eIF4E, the active form, and translational efficiency of eIF4E target transcripts. Reduction of phosphorylated eIF4E by IGF2BP3 depletion was rescued by EIF4E-BP2 depletion. At last, we found an inverse correlation between the expression level of IGF2BP3 and EIF4E-BP2 in human lung adenocarcinoma tissues. Together, these results suggest that IGF2BP3 promotes eIF4E-mediated translational activation through the reduction of EIF4E-BP2 via mRNA degradation, leading to enhanced cell proliferation. This is the first report demonstrating that IGF2BP3 is an RNA-destabilizing factor. Notably, here we provide the first evidence for the functional linkage between two previously well-known cancer biomarkers, IGF2BP3 and eIF4E. PMID:26522719

  1. Regulation of skeletal growth and mineral acquisition by the GH/IGF-1 axis: Lessons from mouse models.

    PubMed

    Yakar, Shoshana; Isaksson, Olle

    2016-06-01

    The growth hormone (GH) and its downstream mediator, the insulin-like growth factor-1 (IGF-1), construct a pleotropic axis affecting growth, metabolism, and organ function. Serum levels of GH/IGF-1 rise during pubertal growth and associate with peak bone acquisition, while during aging their levels decline and associate with bone loss. The GH/IGF-1 axis was extensively studied in numerous biological systems including rodent models and cell cultures. Both hormones act in an endocrine and autocrine/paracrine fashion and understanding their distinct and overlapping contributions to skeletal acquisition is still a matter of debate. GH and IGF-1 exert their effects on osteogenic cells via binding to their cognate receptor, leading to activation of an array of genes that mediate cellular differentiation and function. Both hormones interact with other skeletal regulators, such as sex-steroids, thyroid hormone, and parathyroid hormone, to facilitate skeletal growth and metabolism. In this review we summarized several rodent models of the GH/IGF-1 axis and described key experiments that shed new light on the regulation of skeletal growth by the GH/IGF-1 axis. PMID:26432542

  2. [Differences in dynamics of insulin and insulin-like growth I (IGF-I) receptors internalization in isolated rat hepatocytes].

    PubMed

    2013-01-01

    Insulin and IGF-I are two related peptides performing in the mammalian body functionally different roles of the metabolic and growth hormones, respectively. Internalization of the insulin-receptor complex (IRC) is the most important chain of mechanism of the action of hormone. To elucidate differences in the main stages of internalization of the two related hormones, the internalization dynamics of 125I-insulin and 125I-IGF-I was traced in isolated rat hepatocytes at 37 and 12 degrees C. There were established marked differences in the process of internalization of labeled hormones, which is stimulated by insulin and IGF-I. At 37 degrees C the insulin-stimulated internalization, unlike the process initiated by IGF-I, did not reach the maximal level for 1 h of incubation. However, essential differences in the internalization course of these two related peptide were obvious at the temperature of 12 degrees C. The internalization level of insulin receptors at 12 degrees C decreased by one third in spite of a significant increase of the insulin receptor binding on the hepatocytes plasma membrane. At 12 degrees C a slight decrease of the proportion of intracellular 125I-IGF-I correlated with a decrease in the 125I-IGF-I binding to receptors on the cell membrane. Internalization of IGF-I receptors was not affected by low temperature, as neither its level, nor the rate changed at 12 degrees C. The paradoxical decrease of the insulin-stimulated internalization at low temperature seems to represent a peculiar "inhibition mechanism" of immersion of IRC into the cell, which leads to accumulation of the complexes on the cell surface and possibly to a readjustment of the insulin biological activity. The resistance of internalization of the IGF-I receptor to cold seems to be related to the more ancient origin of this mechanism in the poikilothermal vertebrates. PMID:25509050

  3. [Differences in dynamics of insulin and insulin-like growth I (IGF-I) receptors internalization in isolated rat hepatocytes].

    PubMed

    Kolychev, A P; Ternovskaya, E E; Arsenieva, A V; Shapkina, E V

    2013-01-01

    Insulin and IGF-I are two related peptides performing in the mammalian body functionally different roles of the metabolic and growth hormones, respectively. Internalization of the insulin-receptor complex (IRC) is the most important chain of mechanism of the action of hormone. To elucidate differences in the main stages of internalization of the two related hormones, the internalization dynamics of 125I-insulin and 125I-IGF-I was traced in isolated rat hepatocytes at 37 and 12 degrees C. There were established marked differences in the process of internalization of labeled hormones, which is stimulated by insulin and IGF-I. At 37 degrees C the insulin-stimulated internalization, unlike the process initiated by IGF-I, did not reach the maximal level for 1 h of incubation. However, essential differences in the internalization course of these two related peptide were obvious at the temperature of 12 degrees C. The internalization level of insulin receptors at 12 degrees C decreased by one third in spite of a significant increase of the insulin receptor binding on the hepatocytes plasma membrane. At 12 degrees C a slight decrease of the proportion of intracellular 125I-IGF-I correlated with a decrease in the 125I-IGF-I binding to receptors on the cell membrane. Internalization of IGF-I receptors was not affected by low temperature, as neither its level, nor the rate changed at 12 degrees C. The paradoxical decrease of the insulin-stimulated internalization at low temperature seems to represent a peculiar "inhibition mechanism" of immersion of IRC into the cell, which leads to accumulation of the complexes on the cell surface and possibly to a readjustment of the insulin biological activity. The resistance of internalization of the IGF-I receptor to cold seems to be related to the more ancient origin of this mechanism in the poikilothermal vertebrates. PMID:25490849

  4. Testosterone and Estradiol Regulate Free IGF-I, IGFBP-1 and Dimeric IGF-I/IGFBP-1 Concentrations

    PubMed Central

    Veldhuis, Johannes D.; Frystyk, Jan; Iranmanesh, Ali; Ørskov, Hans

    2005-01-01

    The present study tests the clinical postulate that elevated testosterone (Te) and estradiol (E2) concentrations modulate the effects of constant iv infusion of saline vs recombinant human IGF-I on free IGF-I, IGFBP-1 and dimeric IGF-I/IGFBP-1 concentrations in healthy aging adults. To this end, comparisons were made following administration of placebo (Pl) vs Te in 8 older men (age 61 ± 4 y) and after Pl vs E2 in 8 postmenopausal women (62 ± 3 y). In the saline session: (i) E2 lowered and Te increased total IGF-I; (ii) E2 specifically elevated IGFBP-1 by 1.5-fold and suppressed free IGF-I by 34%; and (iii) E2 increased binary IGF-I/IGFBP-1 by 5-fold more than Te. During IGF-I infusion: (i) total and free IGF-I rose 1.4–2.0 fold [Pl] and 2.1–2.5 fold [Te] more rapidly in men than women; (ii) binary IGF-I/IGFBP-1 increased 3.4-fold more rapidly in men [Te] than women [E2]; and (iii) end-infusion free IGF-I was 1.6-fold higher in men than women. In summary, E2 compared with Te supplementation lowers concentrations of total and ultrafiltratably free IGF-I and elevates those of IGFBP-1 and binary IGF-I/IGFBP-1, thus putatively limiting IGF-I bioavailability. If free IGF-I mediates certain biological actions, then exogenous Te and E2 may modulate the tissue effects of total IGF-I concentrations unequally. PMID:15713723

  5. Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under Hypoxia

    PubMed Central

    Hirakawa, Toshiki; Yashiro, Masakazu; Doi, Yosuke; Kinoshita, Haruhito; Morisaki, Tamami; Fukuoka, Tatsunari; Hasegawa, Tsuyoshi; Kimura, Kenjiro; Amano, Ryosuke; Hirakawa, Kosei

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by its hypovascularity, with an extremely poor prognosis because of its highly invasive nature. PDAC proliferates with abundant stromal cells, suggesting that its invasive activity might be controlled by intercellular interactions between cancer cells and fibroblasts. Using four PDAC cell lines and two pancreas cancer-associated fibroblasts (CAFs), the expression of insulin-like growth factor-1 (IGF1) and IGF1 receptor (IGF1R) was evaluated by RT-PCR, FACScan, western blot, or ELISA. Correlation between IGF1R and the hypoxia marker carbonic anhydrase 9 (CA9) was examined by immunohistochemical staining of 120 pancreatic specimens. The effects of CAFs, IGF1, and IGF1R inhibitors on the motility of cancer cells were examined by wound-healing assay or invasion assay under normoxia (20% O2) and hypoxia (1% O2). IGF1R expression was significantly higher in RWP-1, MiaPaCa-2, and OCUP-AT cells than in Panc-1 cells. Hypoxia increased the expression level of IGF1R in RWP-1, MiaPaCa-2, and OCUP-AT cells. CA9 expression was correlated with IGF1R expression in pancreatic specimens. CAFs produced IGF1 under hypoxia, but PDAC cells did not. A conditioned medium from CAFs, which expressed αSMA, stimulated the migration and invasion ability of MiaPaCa-2, RWP-1, and OCUP-AT cells. The motility of all PDAC cells was greater under hypoxia than under normoxia. The motility-stimulating ability of CAFs was decreased by IGF1R inhibitors. These findings might suggest that pancreas CAFs stimulate the invasion activity of PDAC cells through paracrine IGF1/IGF1R signaling, especially under hypoxia. Therefore the targeting of IGF1R signaling might represent a promising therapeutic approach in IGF1R-dependent PDAC. PMID:27487118

  6. IGF-1 Receptor Inhibitors in Clinical Trials—Early Lessons

    PubMed Central

    Weroha, S. John

    2009-01-01

    The insulin-like growth factor pathway plays a major role in cancer cell proliferation, survival and resistance to anti-cancer therapies in many human malignancies, including breast cancer. As a key signaling component of IGF system, the IGF-1 receptor is the target of several investigational agents in clinical and pre-clinical development. This review will focus on the rationale for targeting the IGF-1 receptor and other components of the IGF-1 system. In addition, we will examine the role of IGF-1 signaling in resistance to clinically important breast cancer therapies, including cytotoxic chemotherapy, hormonal therapy and erbB targeted agents. We will also review the completed and ongoing clinical investigations with IGF-1 receptors inhibitors to date and the utility of these early data in designing future breast cancer studies with IGF-1 signaling inhibition strategies. PMID:19023648

  7. New insights into IGF-1 signaling in the heart.

    PubMed

    Troncoso, Rodrigo; Ibarra, Cristián; Vicencio, Jose Miguel; Jaimovich, Enrique; Lavandero, Sergio

    2014-03-01

    Insulin-like growth factor 1 (IGF-1) signaling regulates contractility, metabolism, hypertrophy, autophagy, senescence, and apoptosis in the heart. IGF-1 deficiency is associated with an increased risk of cardiovascular disease, whereas cardiac activation of IGF-1 receptor (IGF-1R) protects from the detrimental effects of a high-fat diet and myocardial infarction. IGF-1R activates multiple pathways through its intrinsic tyrosine kinase activity and through coupling to heterotrimeric G protein. These pathways involve classic second messengers, phosphorylation cascades, lipid signaling, Ca(2+) transients, and gene expression. In addition, IGF-1R triggers signaling in different subcellular locations including the plasma membrane, perinuclear T tubules, and also in internalized vesicles. In this review, we provide a fresh and updated view of the complex IGF-1 scenario in the heart, including a critical focus on therapeutic strategies. PMID:24380833

  8. Growth Hormone Ameliorates the Radiotherapy-Induced Ovarian Follicular Loss in Rats: Impact on Oxidative Stress, Apoptosis and IGF-1/IGF-1R Axis

    PubMed Central

    Mahran, Yasmen F.; El-Demerdash, Ebtehal; Nada, Ahmed S.; El-Naga, Reem N.; Ali, Azza A.; Abdel-Naim, Ashraf B.

    2015-01-01

    Radiotherapy is one of the standard cytotoxic therapies for cancer. However, it has a profound impact on ovarian function leading to premature ovarian failure and infertility. Since none of the currently available methods for fertility preservation guarantees future fertility, the need for an effective radioprotective agent is highly intensified. The present study investigated the mechanisms of the potential radioprotective effect of growth hormone (GH) on γ irradiation-induced ovarian failure and the impact of the insulin like growth factor 1 (IGF-1) in the underlying protection. Immature female Sprague-Dawley rats were either exposed to single whole body irradiation (3.2 Gy) and/or treated with GH (1 mg/kg s.c). Experimental γ-irradiation produced an array of ovarian dysfunction that was evident by assessment of hormonal changes, follicular development, proliferation marker (PCNA), oxidative stress as well as apoptotic markers. In addition, IGF-1/IGF-1R axis expression was assessed using real-time PCR and immunolocalization techniques. Furthermore, after full maturity, fertility assessment was performed. GH significantly enhanced follicular development and restored anti-Mullerian hormone serum level as compared with the irradiated group. In addition, GH significantly ameliorated the deleterious effects of irradiation on oxidative status, PCNA and apoptosis. Interestingly, GH was shown to enhance the ovarian IGF-1 at transcription and translation levels, a property that contributes significantly to its radioprotective effect. Finally, GH regained the fertility that was lost following irradiation. In conclusion, GH showed a radioprotective effect and rescued the ovarian reserve through increasing local IGF-1 level and counteracting the oxidative stress-mediated apoptosis. PMID:26465611

  9. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1

    NASA Astrophysics Data System (ADS)

    Guan, Jian; Gluckman, Peter; Yang, Panzao; Krissansen, Geoff; Sun, Xueying; Zhou, Yongzhi; Wen, Jingyuan; Phillips, Gemma; Shorten, Paul R.; McMahon, Chris D.; Wake, Graeme C.; Chan, Wendy H. K.; Thomas, Mark F.; Ren, April; Moon, Steve; Liu, Dong-Xu

    2014-03-01

    The homeostasis of insulin-like growth factor-1 (IGF-1) is essential for metabolism, development and survival. Insufficient IGF-1 is associated with poor recovery from wounds whereas excessive IGF-1 contributes to growth of tumours. We have shown that cyclic glycine-proline (cGP), a metabolite of IGF-1, can normalise IGF-1 function by showing its efficacy in improving the recovery from ischemic brain injury in rats and inhibiting the growth of lymphomic tumours in mice. Further investigation in cell culture suggested that cGP promoted the activity of IGF-1 when it was insufficient, but inhibited the activity of IGF-1 when it was excessive. Mathematical modelling revealed that the efficacy of cGP was a modulated IGF-1 effect via changing the binding of IGF-1 to its binding proteins, which dynamically regulates the balance between bioavailable and non-bioavailable IGF-1. Our data reveal a novel mechanism of auto-regulation of IGF-1, which has physiological and pathophysiological consequences and potential pharmacological utility.

  10. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1

    PubMed Central

    Guan, Jian; Gluckman, Peter; Yang, Panzao; Krissansen, Geoff; Sun, Xueying; Zhou, Yongzhi; Wen, Jingyuan; Phillips, Gemma; Shorten, Paul R.; McMahon, Chris D.; Wake, Graeme C.; Chan, Wendy H. K.; Thomas, Mark F.; Ren, April; Moon, Steve; Liu, Dong-Xu

    2014-01-01

    The homeostasis of insulin-like growth factor-1 (IGF-1) is essential for metabolism, development and survival. Insufficient IGF-1 is associated with poor recovery from wounds whereas excessive IGF-1 contributes to growth of tumours. We have shown that cyclic glycine-proline (cGP), a metabolite of IGF-1, can normalise IGF-1 function by showing its efficacy in improving the recovery from ischemic brain injury in rats and inhibiting the growth of lymphomic tumours in mice. Further investigation in cell culture suggested that cGP promoted the activity of IGF-1 when it was insufficient, but inhibited the activity of IGF-1 when it was excessive. Mathematical modelling revealed that the efficacy of cGP was a modulated IGF-1 effect via changing the binding of IGF-1 to its binding proteins, which dynamically regulates the balance between bioavailable and non-bioavailable IGF-1. Our data reveal a novel mechanism of auto-regulation of IGF-1, which has physiological and pathophysiological consequences and potential pharmacological utility. PMID:24633053

  11. Mature IGF-I excels in promoting functional muscle recovery from disuse atrophy compared with pro-IGF-IA

    PubMed Central

    Park, SooHyun; Brisson, Becky K.; Liu, Min; Spinazzola, Janelle M.

    2013-01-01

    Prolonged disuse of skeletal muscle results in atrophy, and once physical activity is resumed, there is increased susceptibility to injury. Insulin-like growth factor-I (IGF-I) is considered a potential therapeutic target to attenuate atrophy during unloading and to enhance rehabilitation upon reloading of skeletal muscles, due to its multipronged actions on satellite cell proliferation, differentiation, and survival, as well as its actions on muscle fibers to boost protein synthesis and inhibit protein degradation. However, the form of IGF-I delivered may alter the success of treatment. Using the hindlimb suspension model of disuse atrophy, we compared the efficacy of two IGF-I forms in protection against atrophy and enhancement of recovery: mature IGF-I (IGF-IS) lacking the COOH-terminal extension, called the E-peptide, and IGF-IA, which is the predominant form retaining the E-peptide. Self-complementary adeno-associated virus harboring the murine Igf1 cDNA constructs were delivered to hindlimbs of adult female C57BL6 mice 3 days prior to hindlimb suspension. Hindlimb muscles were unloaded for 7 days and then reloaded for 3, 7, and 14 days. Loss of muscle mass following suspension was not prevented by either IGF-I construct. However, IGF-IS expression maintained soleus muscle force production. Further, IGF-IS treatment caused rapid recovery of muscle fiber morphology during reloading and maintained muscle strength. Analysis of gene expression revealed that IGF-IS expression accelerated the downregulation of atrophy-related genes compared with untreated or IGF-IA-treated samples. We conclude that mature-IGF-I may be a better option than pro-IGF-IA to promote skeletal muscle recovery following disuse atrophy. PMID:24371018

  12. IGF-1 receptor inhibition by picropodophyllin in medulloblastoma

    SciTech Connect

    Ohshima-Hosoyama, Sachiko; Hosoyama, Tohru; Nelon, Laura D.; Keller, Charles

    2010-09-03

    Research highlights: {yields} Igf1r is overexpressed and activated in a Sonic Hedgehog driven model of medulloblastoma. {yields} Picropodophyllin targets and abrogates IGF signaling in medulloblastoma. {yields} Picropodophyllin inhibits medulloblastoma tumor cell growth by induction of apoptosis. -- Abstract: The insulin-like growth factor-1 receptor (Igf1r) is a multifunctional membrane-associated tyrosine kinase associated with regulation of transformation, proliferation, differentiation and apoptosis. Increased IGF pathway activity has been reported in human and murine medulloblastoma. Tumors from our genetically-engineered medulloblastoma mouse model over-express Igf1r, and thus this mouse model is a good platform with which to study the role of Igf1r in tumor progression. We hypothesize that inhibition of IGF pathway in medulloblastoma can slow or inhibit tumor growth and metastasis. To test our hypothesis, we tested the role of IGF in tumor growth in vitro by treatment with the tyrosine kinase small molecule inhibitor, picropodophyllin (PPP), which strongly inhibits the IGF pathway. Our results demonstrate that PPP-mediated downregulation of the IGF pathway inhibits mouse tumor cell growth and induces apoptotic cell death in vitro in primary medulloblastoma cultures that are most reflective of tumor cell behavior in vivo.

  13. Neuroprotective levels of IGF-1 exacerbate epileptogenesis after brain injury.

    PubMed

    Song, Yu; Pimentel, Corrin; Walters, Katherine; Boller, Lauren; Ghiasvand, Shabnam; Liu, Jing; Staley, Kevin J; Berdichevsky, Yevgeny

    2016-01-01

    Exogenous Insulin-Like Growth Factor-1 (IGF-1) is neuroprotective in animal models of brain injury, and has been considered as a potential therapeutic. Akt-mTOR and MAPK are downstream targets of IGF-1 signaling that are activated after brain injury. However, both brain injury and mTOR are linked to epilepsy, raising the possibility that IGF-1 may be epileptogenic. Here, we considered the role of IGF-1 in development of epilepsy after brain injury, using the organotypic hippocampal culture model of post-traumatic epileptogenesis. We found that IGF-1 was neuroprotective within a few days of injury but that long-term IGF-1 treatment was pro-epileptic. Pro-epileptic effects of IGF-1 were mediated by Akt-mTOR signaling. We also found that IGF-1 - mediated increase in epileptic activity led to neurotoxicity. The dualistic nature of effects of IGF-1 treatment demonstrates that anabolic enhancement through IGF-1 activation of mTOR cascade can be beneficial or harmful depending on the stage of the disease. Our findings suggest that epilepsy risk may need to be considered in the design of neuroprotective treatments for brain injury. PMID:27561791

  14. Neuroprotective levels of IGF-1 exacerbate epileptogenesis after brain injury

    PubMed Central

    Song, Yu; Pimentel, Corrin; Walters, Katherine; Boller, Lauren; Ghiasvand, Shabnam; Liu, Jing; Staley, Kevin J.; Berdichevsky, Yevgeny

    2016-01-01

    Exogenous Insulin-Like Growth Factor-1 (IGF-1) is neuroprotective in animal models of brain injury, and has been considered as a potential therapeutic. Akt-mTOR and MAPK are downstream targets of IGF-1 signaling that are activated after brain injury. However, both brain injury and mTOR are linked to epilepsy, raising the possibility that IGF-1 may be epileptogenic. Here, we considered the role of IGF-1 in development of epilepsy after brain injury, using the organotypic hippocampal culture model of post-traumatic epileptogenesis. We found that IGF-1 was neuroprotective within a few days of injury but that long-term IGF-1 treatment was pro-epileptic. Pro-epileptic effects of IGF-1 were mediated by Akt-mTOR signaling. We also found that IGF-1 – mediated increase in epileptic activity led to neurotoxicity. The dualistic nature of effects of IGF-1 treatment demonstrates that anabolic enhancement through IGF-1 activation of mTOR cascade can be beneficial or harmful depending on the stage of the disease. Our findings suggest that epilepsy risk may need to be considered in the design of neuroprotective treatments for brain injury. PMID:27561791

  15. Effects of space flight and IGF-1 on immune function

    NASA Astrophysics Data System (ADS)

    1999-01-01

    We tested the hypothesis that insulin-like growth factor-1 (IGF-1) would ameliorate space flight-induced effects on the immune system. Twelve male, Sprague-Dawley rats, surgically implanted with mini osmotic pumps, were subjected to space flight for 10 days on STS-77. Six rats received 10 mg/kg/day of IGF-1 and 6 rats received saline. Flight animals had a lymphocytopenia and granulocytosis which were reversed by IGF-1. Flight animals had significantly higher corticosterone levels than ground controls but IGF-1 did not impact this stress hormone. Therefore, the reversed granulocytosis did not correlate with serum corticosterone. Space flight and IGF-1 also combined to induce a monocytopenia that was not evident in ground control animals treated with IGF-1 or in animals subjected to space flight but given physiological saline. There was a significant increase in spleen weights in vivarium animals treated with IGF-1, however, this change did not occur in flight animals. We observed reduced agonist-induced lymph node cell proliferation by cells from flight animals compared to ground controls. The reduced proliferation was not augmented by IGF-1 treatment. There was enhanced secretion of TNF, IL-6 and NO by flight-animal peritoneal macrophages compared to vivarium controls, however, O2- secretion was not affected. These data suggest that IGF-1 can ameliorate some of the effects of space flight but that space flight can also impact the normal response to IGF-1.

  16. Differential effects of STAT proteins on growth hormone-mediated IGF-I gene expression.

    PubMed

    Varco-Merth, Ben; Rotwein, Peter

    2014-11-01

    Growth hormone (GH) plays a key role regulating somatic growth and in controlling metabolism and other physiological processes in humans and other animal species. GH acts by binding to the extracellular part of its transmembrane receptor, leading to induction of multiple intracellular signal transduction pathways that culminate in changes in gene and protein expression. A key agent in GH-stimulated growth is the latent transcription factor signal transducer and activator of transcription (STAT) 5B, one of four STAT proteins induced by the GH receptor in cultured cells and in vivo. As shown by genetic and biochemical studies, GH-activated STAT5B promotes transcription of the gene encoding the critical growth peptide, insulin-like growth factor-I (IGF-I), and natural null mutations of STAT5B in humans lead to growth failure accompanied by diminished IGF-I expression. Here we have examined the possibility that other GH-activated STATs can enhance IGF-I gene transcription, and thus potentially contribute to GH-regulated somatic growth. We find that human STAT5A is nearly identical to STAT5B in its biochemical and functional responses to GH but that STAT1 and STAT3 show a weaker profile of in vitro binding to STAT DNA elements from the IGF-I gene than STAT5B, and are less potent inducers of gene transcription through these elements. Taken together, our results offer a molecular explanation for why STAT5B is a key in vivo mediator of GH-activated IGF-I gene transcription and thus of GH-regulated somatic growth. PMID:25205818

  17. IGF-1 drives chromogranin A secretion via activation of Arf1 in human neuroendocrine tumour cells

    PubMed Central

    Münzberg, Christin; Höhn, Katharina; Krndija, Denis; Maaß, Ulrike; Bartsch, Detlef K; Slater, Emily P; Oswald, Franz; Walther, Paul; Seufferlein, Thomas; von Wichert, Götz

    2015-01-01

    Hypersecretion is the major symptom of functional neuroendocrine tumours. The mechanisms that contribute to this excessive secretion of hormones are still elusive. A key event in secretion is the exit of secretory products from the Golgi apparatus. ADP-ribosylation factor (Arf) GTPases are known to control vesicle budding and trafficking, and have a leading function in the regulation of formation of secretory granula at the Golgi. Here, we show that Arf1 is the predominant Arf protein family member expressed in the neuroendocrine pancreatic tumour cell lines BON and QGP-1. In BON cells Arf1 colocalizes with Golgi markers as well as chromogranin A, and shows significant basal activity. The inhibition of Arf1 activity or expression significantly impaired secretion of chromogranin A. Furthermore, we show that the insulin-like growth factor 1 (IGF-1), a major regulator of growth and secretion in BON cells, induces Arf1 activity. We found that activation of Arf1 upon IGF-1 receptor stimulation is mediated by MEK/ERK signalling pathway in BON and QGP-1 cells. Moreover, the activity of Arf1 in BON cells is mediated by autocrinely secreted IGF-1, and concomitantly, autocrine IGF1 secretion is maintained by Arf1 activity. In summary, our data indicate an important regulatory role for Arf1 at the Golgi in hypersecretion in neuroendocrine cancer cells. PMID:25754106

  18. MicroRNAs modulated by local mIGF-1 expression in mdx dystrophic mice

    PubMed Central

    Pelosi, Laura; Coggi, Angela; Forcina, Laura; Musarò, Antonio

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a X-linked genetic disease in which the absence of dystrophin leads to progressive lethal skeletal muscle degeneration. It has been demonstrated that among genes which are important for proper muscle development and function, micro-RNAs (miRNAs) play a crucial role. Moreover, altered levels of miRNAs were found in several muscular disorders, including DMD. A specific group of miRNAs, whose expression depends on dystrophin levels and whose deregulation explains several DMD pathogenetic traits, has been identified. Here, we addressed whether the anabolic activity of mIGF-1 on dystrophic muscle is associated with modulation of microRNAs expression. We demonstrated that some microRNAs are strictly linked to the dystrophin expression and are not modulated by mIGF-1 expression. In contrast, local expression of mIGF-1 promotes the modulation of other microRNAs, such as miR-206 and miR-24, along with the modulation of muscle specific genes, which are associated with maturation of regenerating fibers and with the stabilization of the differentiated muscle phenotype. These data suggest that mIGF-1, modifying the expression of some of the active players of muscle homeostasis, is able, even in absence of dystrophin expression, to activate circuitries that confer robustness to dystrophic muscle. PMID:25999854

  19. The Association between IGF-1 Polymorphisms, IGF-1 Serum Levels, and Cognitive Functions in Healthy Adults: The Amsterdam Growth and Health Longitudinal Study

    PubMed Central

    Licht, Carmilla M. M.; van Turenhout, Lise C.; Deijen, Jan Berend; Koppes, Lando L. J.; van Mechelen, Willem; Twisk, Jos W. R.; Drent, Madeleine L.

    2014-01-01

    Several studies have demonstrated an association between polymorphisms in the insulin-like growth factor-1 (IGF-1) gene and IGF-1 serum levels. IGF-1 levels have been associated with cognitive functioning in older persons and growth hormone deficient patients. The present study investigates whether IGF-1 polymorphisms, IGF-1 levels, and cognition are interconnected in healthy adults. Data of 277 participants (mean age: 42.4 years) of the Amsterdam Growth and Health Longitudinal Study on IGF-1 promoter polymorphisms, IGF-1 serum level, spatial working memory (SWM), paired associate learning (PAL), and IQ tests were analyzed. (M)ANOVAs were applied to confirm the associations between IGF-1 polymorphisms and IGF-1 levels and between IGF-1 levels and cognition. Three groups were distinguished based on specific IGF-1 polymorphism alleles: a homozygote 192 bp/192 bp genotype, a heterozygote 192 bp/x genotype, and a noncarrier x/x genotype. Although different IGF-1 levels were found for the three genotypes, performance on all cognitive tasks and IQ measures was similar. Despite the associations between IGF-1 polymorphisms and IGF-1 levels, no association was found between cognition and IGF-1 levels. It seems that IGF-1 does not play a role in the cognitive performance of healthy middle-aged adults. Possible, IGF-1 fulfills a more developmental and protective role in cognition which becomes apparent during childhood, old-age, or disease. PMID:25114679

  20. Recombinant IGF-I: Past, present and future.

    PubMed

    Bright, George M

    2016-06-01

    Normal linear growth in humans requires GH and IGF-I. Diminished GH action resulting in reduced availability of IGF-I and IGF-binding proteins is the hallmarks of GH Insensitivity Syndromes (GHIS). The deficiencies are the perceived mechanisms for the growth failure of affected patients and the therapeutic targets for the restoration of normal growth. Early treatment attempts with pituitary-derived GH had limited effects in GHIS patients. Recombinant human insulin-like growth factor-I (rhIGF-I) treatment initially provides accelerated growth to GHIS children and provides substantial benefit. But, in general, catch up growth is less substantial with rhIGF-I treatment of GHIS than with rhGH treatment of GH Deficiency. Few classic GHIS patients have reached heights in the normal range (height SD score between -2.0 SD and +2.0 SD) with rhIGF-I monotherapy. A potential explanation is that while rhIGF-I treatment increases circulating concentrations of IGF-1 and IGFBP-3, such treatment reduces endogenous GH levels by negative feedback inhibition of pituitary GH release. In as much as both GH and IGF-I are required for good catch up growth, the loss of any residual GH signaling during IGF-I monotherapy in GHIS patients may attenuate possible catch up growth. Consistent with this explanation is the finding that, as predicted by the preclinical studies by Ross Clark, combination of rhGH & rhIGF-1 provides better growth responses than rhIGF-1 monotherapy in prepubertal children with short stature and low IGF-I levels despite normal stimulated GH responses. In the future, rhGH and rhIGF-I combination therapy can potentially improve growth outcomes over that seen with rhIGF-I monotherapy in all GHIS patients except in those with a total lack of functional GH signaling. Future alternative treatments for GHIS subjects may also include the use of post-growth hormone receptor signaling agonists which restore both GH signaling and IGF-I exposures or the addition of long-acting rh

  1. IGF-IR and its inhibitors in gastrointestinal carcinomas (Review)

    PubMed Central

    BAO, XIAO HONG; NAOMOTO, YOSHIO; HAO, HUI FANG; WATANABE, NOBUYUKI; SAKURAMA, KAZUFUMI; NOMA, KAZUHIRO; MOTOKI, TAKAYUKI; TOMONO, YASUKO; FUKAZAWA, TAKUYA; SHIRAKAWA, YASUHIRO; YAMATSUJI, TOMOKI; MATSUOKA, JUNJI; TAKAOKA, MUNENORI

    2010-01-01

    The type I insulin-like growth factor receptor (IGF-IR) and its associated signaling system play a significant role in tumorigenesis, tumor survival and progression, and cancer therapeutic resistance, and thus has provoked great interest as a promising target for cancer treatment. In this report we present the role of IGF-IR in gastrointestinal carcinomas whose pathology has been identified as tightly correlated with an abnormal expression and activation of IGF-IR. Reported data from experimental studies suggest the feasibility of targeted IGF-IR therapy in gastrointestinal carcinomas. Many types of inhibitors against IGF-IR have been developed. Inhibitors with anti-IGF-IR monoclonal antibodies and tyrosine kinase inhibitors currently undergoing preclinical and clinical evolution are also reviewed. PMID:22966282

  2. MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells.

    PubMed

    Das, Falguni; Dey, Nirmalya; Bera, Amit; Kasinath, Balakuntalam S; Ghosh-Choudhury, Nandini; Choudhury, Goutam Ghosh

    2016-07-01

    Elevated IGF-1/insulin-like growth factor-1 receptor (IGF-1R) autocrine/paracrine signaling in patients with renal cell carcinoma is associated with poor prognosis of the disease independent of their von Hippel-Lindau (VHL) status. Increased expression of IGF-1R in renal cancer cells correlates with their potency of tumor development and progression. The mechanism by which expression of IGF-1R is increased in renal carcinoma is not known. We report that VHL-deficient and VHL-positive renal cancer cells possess significantly decreased levels of mature, pre-, and pri-miR-214 than normal proximal tubular epithelial cells. We identified an miR-214 recognition element in the 3'UTR of IGF-1R mRNA and confirmed its responsiveness to miR-214. Overexpression of miR-214 decreased the IGF-1R protein levels, resulting in the inhibition of Akt kinase activity in both types of renal cancer cells. IGF-1 provoked phosphorylation and inactivation of PRAS40 in an Akt-dependent manner, leading to the activation of mTORC1 signal transduction to increase phosphorylation of S6 kinase and 4EBP-1. Phosphorylation-deficient mutants of PRAS40 and 4EBP-1 significantly inhibited IGF-1R-driven proliferation of renal cancer cells. Expression of miR-214 suppressed IGF-1R-induced phosphorylation of PRAS40, S6 kinase, and 4EBP-1, indicating inhibition of mTORC1 activity. Finally, miR-214 significantly blocked IGF-1R-forced renal cancer cell proliferation, which was reversed by expression of 3'UTR-less IGF-1R and constitutively active mTORC1. Together, our results identify a reciprocal regulation of IGF-1R levels and miR-214 expression in renal cancer cells independent of VHL status. Our data provide evidence for a novel mechanism for IGF-1R-driven renal cancer cell proliferation involving miR-214 and mTORC1. PMID:27226530

  3. Insulin-like growth factor binding protein-5 (IGFBP-5) interacts with thrombospondin-1 to induce negative regulatory effects on IGF-I actions.

    PubMed

    Moralez, Anna M; Maile, Laura A; Clarke, Jane; Busby, Walker H; Clemmons, David R

    2005-05-01

    effect on TS-1 binding to IAP. Further analysis showed that IGFBP-5 addition altered the ability of TS-1 to modulate the SHPS-1/IAP interaction. When the IGFBP-5 mutant that did not bind to IGF-I was incubated with TS-1 and IGF-I, it inhibited the capacity of TS-1 to enhance the IGF-I receptor phosphorylation and MAP kinase activation in response to IGF-I. In contrast, the IGFBP-5 mutant that did not bind to TS-1 had no effect on IGF-I stimulated IGF-I receptor phosphorylation or MAP kinase activation. These results indicate that IGFBP-5 inhibits the binding of TS-1 to IAP, and this results in an alteration of the ability of TS-1 to modulate the disruption of the IAP/SHPS-1 interaction which leads to attenuation of the ability of TS-1 to enhance cellular responsiveness to IGF-I. PMID:15700281

  4. Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist.

    PubMed

    Frago, Susana; Nicholls, Ryan D; Strickland, Madeleine; Hughes, Jennifer; Williams, Christopher; Garner, Lee; Surakhy, Mirvat; Maclean, Rory; Rezgui, Dellel; Prince, Stuart N; Zaccheo, Oliver J; Ebner, Daniel; Sanegre, Sabina; Yu, Sheng; Buffa, Francesca M; Crump, Matthew P; Hassan, Andrew Bassim

    2016-05-17

    Among the 15 extracellular domains of the mannose 6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R), domain 11 has evolved a binding site for IGF2 to negatively regulate ligand bioavailability and mammalian growth. Despite the highly evolved structural loops of the IGF2:domain 11 binding site, affinity-enhancing AB loop mutations suggest that binding is modifiable. Here we examine the extent to which IGF2:domain 11 affinity, and its specificity over IGF1, can be enhanced, and we examine the structural basis of the mechanistic and functional consequences. Domain 11 binding loop mutants were selected by yeast surface display combined with high-resolution structure-based predictions, and validated by surface plasmon resonance. We discovered previously unidentified mutations in the ligand-interacting surface binding loops (AB, CD, FG, and HI). Five combined mutations increased rigidity of the AB loop, as confirmed by NMR. When added to three independently identified CD and FG loop mutations that reduced the koff value by twofold, these mutations resulted in an overall selective 100-fold improvement in affinity. The structural basis of the evolved affinity was improved shape complementarity established by interloop (AB-CD) and intraloop (FG-FG) side chain interactions. The high affinity of the combinatorial domain 11 Fc fusion proteins functioned as ligand-soluble antagonists or traps that depleted pathological IGF2 isoforms from serum and abrogated IGF2-dependent signaling in vivo. An evolved and reengineered high-specificity M6P/IGF2R domain 11 binding site for IGF2 may improve therapeutic targeting of the frequent IGF2 gain of function observed in human cancer. PMID:27140600

  5. Sequence-specific targeting of IGF-I and IGF-IR genes by camptothecins

    PubMed Central

    Oussedik, Kahina; François, Jean-Christophe; Halby, Ludovic; Senamaud-Beaufort, Catherine; Toutirais, Géraldine; Dallavalle, Sabrina; Pommier, Yves; Pisano, Claudio; Arimondo, Paola B.

    2010-01-01

    We and others have clearly demonstrated that a topoisomerase I (Top1) inhibitor, such as camptothecin (CPT), coupled to a triplex-forming oligonucleotide (TFO) through a suitable linker can be used to cause site-specific cleavage of the targeted DNA sequence in in vitro models. Here we evaluated whether these molecular tools induce sequence-specific DNA damage in a genome context. We targeted the insulin-like growth factor (IGF)-I axis and in particular promoter 1 of IGF-I and intron 2 of type 1 insulin-like growth factor receptor (IGF-IR) in cancer cells. The IGF axis molecules represent important targets for anticancer strategies, because of their central role in oncogenic maintenance and metastasis processes. We chemically attached 2 CPT derivatives to 2 TFOs. Both conjugates efficiently blocked gene expression in cells, reducing the quantity of mRNA transcribed by 70–80%, as measured by quantitative RT-PCR. We confirmed that the inhibitory mechanism of these TFO conjugates was mediated by Top1-induced cleavage through the use of RNA interference experiments and a camptothecin-resistant cell line. In addition, induction of phospho-H2AX foci supports the DNA-damaging activity of TFO-CPT conjugates at specific sites. The evaluated conjugates induce a specific DNA damage at the target gene mediated by Top1.—Oussedik, K., François, J.-C., Halby, L., Senamaud-Beaufort, C., Toutirais, G., Dallavalle, S., Pommier, Y., Pisano, C., Arimondo, P. B. Sequence-specific targeting of IGF-I and IGF-IR genes by camptothecins. PMID:20179147

  6. Characterization of the Igf-II Binding Site of the IGF-II/MAN-6-P Receptor Extracellular Domain.

    NASA Astrophysics Data System (ADS)

    Garmroudi, Farideh

    1995-01-01

    In mammals, insulin-like growth factor II (IGF -II) and glycoproteins bearing the mannose 6-phosphate (Man -6-P) recognition marker bind with high affinity to the same receptor. The functional consequences of IGF-II binding to the receptor at the cell surface are not clear. In these studies, we sought to broaden our understanding of the functional regions of the receptor regarding its IGF -II binding site. The IGF-II binding/cross-linking domain of the IGF-II/Man-6-P receptor was mapped by sequencing receptor fragments covalently attached to IGF-II. Purified rat placental or bovine liver receptors were affinity-labeled, with ^{125}I-IGF-II and digested with endoproteinase Glu-C. Analysis of digests by gel electrophoresis revealed a major radiolabeled band of 18 kDa, which was purified by gel filtration chromatography followed by reverse-phase HPLC and electroblotting. Sequence analysis revealed that, the peptide S(H)VNSXPMF, located within extracellular repeat 10 and beginning with serine 1488 of the bovine receptor, was the best candidate for the IGF-II cross-linked peptide. These data indicated that residues within repeats 10-11 were important for IGF -II binding. To define the location of the IGF-II binding site further, a nested set of six human receptor cDNA constructs was designed to produce epitope-tagged fusion proteins encompassing the region between repeats 8 and 11 of the human IGF-II/Man-6-P receptor extracellular domain. These truncated receptors were transiently expressed in COS-7 cells, immunoprecipitated and analyzed for their abilities to bind and cross-link to IGF-II. All of the constructs were capable of binding/cross-linking to IGF-II, except for the 9.0-11 construct. Displacement curve analysis indicated that the truncated receptors were approximately equivalent in IGF-II binding affinity, but were of 5- to 10-fold lower affinity than full-length receptors. Sequencing of the 9.0-11 construct indicated the presence of a point mutation

  7. Monotreme IGF2 expression and ancestral origin of genomic imprinting.

    PubMed

    Killian, J K; Nolan, C M; Stewart, N; Munday, B L; Andersen, N A; Nicol, S; Jirtle, R L

    2001-08-15

    IGF2 (insulin-like growth factor 2) and M6P/IGF2R (mannose 6-phosphate/insulin-like growth factor 2 receptor) are imprinted in marsupials and eutherians but not in birds. These results along with the absence of M6P/IGF2R imprinting in the egg-laying monotremes indicate that the parental imprinting of fetal growth-regulatory genes may be unique to viviparous mammals. In this investigation, we have cloned IGF2 from two monotreme mammals, the platypus and echidna, to further investigate the origin of imprinting. We report herein that like M6P/IGF2R, IGF2 is not imprinted in monotremes. Thus, although IGF2 encodes for a highly conserved growth factor in chordates, it is only imprinted in therian mammals. These findings support a concurrent origin of IGF2 and M6P/IGF2R imprinting in the late Jurassic/early Cretaceous period. The absence of imprinting in monotremes, despite apparent interparental conflicts over maternal-offspring exchange, argues that a fortuitous congruency of genetic and epigenetic events may have limited the phylogenetic breadth of genomic imprinting to therian mammals. J. Exp. Zool. (Mol. Dev. Evol.) 291:205-212, 2001. PMID:11479919

  8. PKC{eta} is a negative regulator of AKT inhibiting the IGF-I induced proliferation

    SciTech Connect

    Shahaf, Galit; Rotem-Dai, Noa; Koifman, Gabriela; Raveh-Amit, Hadas; Frost, Sigal A.; Livneh, Etta

    2012-04-15

    The PI3K-AKT pathway is frequently activated in human cancers, including breast cancer, and its activation appears to be critical for tumor maintenance. Some malignant cells are dependent on activated AKT for their survival; tumors exhibiting elevated AKT activity show sensitivity to its inhibition, providing an Achilles heel for their treatment. Here we show that the PKC{eta} isoform is a negative regulator of the AKT signaling pathway. The IGF-I induced phosphorylation on Ser473 of AKT was inhibited by the PKC{eta}-induced expression in MCF-7 breast adenocarcinoma cancer cells. This was further confirmed in shRNA PKC{eta}-knocked-down MCF-7 cells, demonstrating elevated phosphorylation on AKT Ser473. While PKC{eta} exhibited negative regulation on AKT phosphorylation it did not alter the IGF-I induced ERK phosphorylation. However, it enhanced ERK phosphorylation when stimulated by PDGF. Moreover, its effects on IGF-I/AKT and PDGF/ERK pathways were in correlation with cell proliferation. We further show that both PKC{eta} and IGF-I confer protection against UV-induced apoptosis and cell death having additive effects. Although the protective effect of IGF-I involved activation of AKT, it was not affected by PKC{eta} expression, suggesting that PKC{eta} acts through a different route to increase cell survival. Hence, our studies show that PKC{eta} provides negative control on AKT pathway leading to reduced cell proliferation, and further suggest that its presence/absence in breast cancer cells will affect cell death, which could be of therapeutic value.

  9. IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation.

    PubMed

    Xi, Gang; Shen, Xinchun; Rosen, Clifford J; Clemmons, David R

    2016-06-01

    Insulin like growth factor I (IGF-I) and insulin like growth factor binding protein-2 (IGFBP-2) function coordinately to stimulate AKT and osteoblast differentiation. IGFBP-2 binding to receptor protein tyrosine phosphatase β (RPTPβ) stimulates polymerization and inactivation of phosphatase activity. Because phosphatase and tensin homolog (PTEN) is the primary target of RPTPβ, this leads to enhanced PTEN tyrosine phosphorylation and inactivation. However RPTPβ inactivation also requires IGF-I receptor activation. The current studies were undertaken to determine the mechanism by which IGF-I mediates changes in RPTPβ function in osteoblasts. IGFBP-2/IGF-I stimulated vimentin binding to RPTPβ and this was required for RPTPβ polymerization. Vimentin serine phosphorylation mediated its binding to RPTPβ and PKCζ was identified as the kinase that phosphorylated vimentin. To determine the mechanism underlying IGF-I stimulation of PKCζ-mediated vimentin phosphorylation, we focused on insulin receptor substrate-1 (IRS-1). IGF-I stimulated IRS-1 phosphorylation and recruitment of PKCζ and vimentin to phospho-IRS-1. IRS-1 immunoprecipitates containing PKCζ and vimentin were used to confirm that activated PKCζ directly phosphorylated vimentin. PKCζ does not contain a SH-2 domain that is required to bind to phospho-IRS-1. To determine the mechanism of PKCζ recruitment we analyzed the role of p62 (a PKCζ binding protein) that contains a SH2 domain. Exposure to differentiation medium plus IGF-I stimulated PKCζ/p62 association. Subsequent analysis showed the p62/PKCζ complex was co-recruited to IRS-1. Peptides that disrupted p62/PKCζ or p62/IRS-1 inhibited IGF-I/IGFBP-2 stimulated PKCζ activation, vimentin phosphorylation, PTEN tyrosine phosphorylation, AKT activation, and osteoblast differentiation. The importance of these signaling events for differentiation was confirmed in primary mouse calvarial osteoblasts. These results demonstrate the cooperative

  10. Decreased glycolate oxidase activity leads to altered carbon allocation and leaf senescence after a transfer from high CO2 to ambient air in Arabidopsis thaliana.

    PubMed

    Dellero, Younès; Jossier, Mathieu; Glab, Nathalie; Oury, Céline; Tcherkez, Guillaume; Hodges, Michael

    2016-05-01

    Metabolic and physiological analyses of Arabidopsis thaliana glycolate oxidase (GOX) mutant leaves were performed to understand the development of the photorespiratory phenotype after transfer from high CO2 to air. We show that two Arabidopsis genes, GOX1 and GOX2, share a redundant photorespiratory role. Air-grown single gox1 and gox2 mutants grew normally and no significant differences in leaf metabolic levels and photosynthetic activities were found when compared with wild-type plants. To study the impact of a highly reduced GOX activity on plant metabolism, both GOX1 and GOX2 expression was knocked-down using an artificial miRNA strategy. Air-grown amiRgox1/2 plants with a residual 5% GOX activity exhibited a severe growth phenotype. When high-CO2-grown adult plants were transferred to air, the photosynthetic activity of amiRgox1/2 was rapidly reduced to 50% of control levels, and a high non-photochemical chlorophyll fluorescence quenching was maintained. (13)C-labeling revealed that daily assimilated carbon accumulated in glycolate, leading to reduced carbon allocation to sugars, organic acids, and amino acids. Such changes were not always mirrored in leaf total metabolite levels, since many soluble amino acids increased after transfer, while total soluble protein, RuBisCO (ribulose-1,5-bisphosphate carboxylase/oxygenase), and chlorophyll amounts decreased in amiRgox1/2 plants. The senescence marker, SAG12, was induced only in amiRgox1/2 rosettes after transfer to air. The expression of maize photorespiratory GOX in amiRgox1/2 abolished all observed phenotypes. The results indicate that the inhibition of the photorespiratory cycle negatively impacts photosynthesis, alters carbon allocation, and leads to early senescence in old rosette leaves. PMID:26896850

  11. Sequence-specific targeting of IGF-I and IGF-IR genes by camptothecins.

    PubMed

    Oussedik, Kahina; François, Jean-Christophe; Halby, Ludovic; Senamaud-Beaufort, Catherine; Toutirais, Géraldine; Dallavalle, Sabrina; Pommier, Yves; Pisano, Claudio; Arimondo, Paola B

    2010-07-01

    We and others have clearly demonstrated that a topoisomerase I (Top1) inhibitor, such as camptothecin (CPT), coupled to a triplex-forming oligonucleotide (TFO) through a suitable linker can be used to cause site-specific cleavage of the targeted DNA sequence in in vitro models. Here we evaluated whether these molecular tools induce sequence-specific DNA damage in a genome context. We targeted the insulin-like growth factor (IGF)-I axis and in particular promoter 1 of IGF-I and intron 2 of type 1 insulin-like growth factor receptor (IGF-IR) in cancer cells. The IGF axis molecules represent important targets for anticancer strategies, because of their central role in oncogenic maintenance and metastasis processes. We chemically attached 2 CPT derivatives to 2 TFOs. Both conjugates efficiently blocked gene expression in cells, reducing the quantity of mRNA transcribed by 70-80%, as measured by quantitative RT-PCR. We confirmed that the inhibitory mechanism of these TFO conjugates was mediated by Top1-induced cleavage through the use of RNA interference experiments and a camptothecin-resistant cell line. In addition, induction of phospho-H2AX foci supports the DNA-damaging activity of TFO-CPT conjugates at specific sites. The evaluated conjugates induce a specific DNA damage at the target gene mediated by Top1. PMID:20179147

  12. Association analysis of the IGF1 gene with childhood growth, IGF-1 concentrations and type 1 diabetes

    PubMed Central

    Vella, A.; Bouatia-Naji, N.; Heude, B.; Cooper, J. D.; Lowe, C. E.; Petry, C.; Ring, S. M.; Dunger, D. B.; Todd, J. A.

    2008-01-01

    Aims/hypothesis Insulin-like growth factor-1 is a major childhood growth factor and promotes pancreatic islet cell survival and growth in vitro. We hypothesised that genetic variation in IGF1 might be associated with childhood growth, glucose metabolism and type 1 diabetes risk. We therefore examined the association between common genetic variation in IGF1 and predisposition to type 1 diabetes, childhood growth and metabolism. Materials and methods Variants in IGF1 were identified by direct resequencing of the exons, exon–intron boundaries and 5′ and 3′ regions in 32 unrelated type 1 diabetes patients. A tagging subset of these variants was genotyped in a collection of type 1 diabetes families (3,121 parent–child trios). We also genotyped a previously reported CA repeat in the region 5′ to IGF1. A subset of seven tag single nucleotide polymorphism (SNPs) that captured variants with minor allele frequency (MAF) ≥0.05 was genotyped in 902 children from the Avon Longitudinal Study of Parents And Children with data on growth, IGF-1 concentrations, insulin secretion and insulin action. Results Resequencing detected 27 SNPs in IGF1, of which 11 had a MAF > 0.05 and were novel. Variants with MAF ≥ 0.10 were captured by a set of four tag-SNPs. These SNPs showed no association with type 1 diabetes. In children, global variation in IGF1 was weakly associated with IGF-1 concentrations, but not with other phenotypes. The CA repeat in the region 5′ to IGF1 showed no association with any phenotype. Conclusions/interpretation Common genetic variation in IGF1 alters IGF-1 concentrations but is not associated with growth, glucose metabolism or type 1 diabetes. Electronic supplementary material The online version of this article (doi:10.1007/s00125-008-0970-7) contains supplementary material, which is available to authorised users. PMID:18317720

  13. The coordinate cellular response to insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-2 (IGFBP-2) is regulated through vimentin binding to receptor tyrosine phosphatase β (RPTPβ).

    PubMed

    Shen, Xinchun; Xi, Gang; Wai, Christine; Clemmons, David R

    2015-05-01

    Insulin-like growth factor-binding protein-2 (IGFBP-2) functions coordinately with IGF-I to stimulate cellular proliferation and differentiation. IGFBP-2 binds to receptor tyrosine phosphatase β (RPTPβ), and this binding in conjunction with IGF-I receptor stimulation induces RPTPβ polymerization leading to phosphatase and tensin homolog inactivation, AKT stimulation, and enhanced cell proliferation. To determine the mechanism by which RPTPβ polymerization is regulated, we analyzed the protein(s) that associated with RPTPβ in response to IGF-I and IGFBP-2 in vascular smooth muscle cells. Proteomic experiments revealed that IGF-I stimulated the intermediate filament protein vimentin to bind to RPTPβ, and knockdown of vimentin resulted in failure of IGFBP-2 and IGF-I to stimulate RPTPβ polymerization. Knockdown of IGFBP-2 or inhibition of IGF-IR tyrosine kinase disrupted vimentin/RPTPβ association. Vimentin binding to RPTPβ was mediated through vimentin serine phosphorylation. The serine threonine kinase PKCζ was recruited to vimentin in response to IGF-I and inhibition of PKCζ activation blocked these signaling events. A cell-permeable peptide that contained the vimentin phosphorylation site disrupted vimentin/RPTPβ association, and IGF-I stimulated RPTPβ polymerization and AKT activation. Integrin-linked kinase recruited PKCζ to SHPS-1-associated vimentin in response to IGF-I and inhibition of integrin-linked kinase/PKCζ association reduced vimentin serine phosphorylation. PKCζ stimulation of vimentin phosphorylation required high glucose and vimentin/RPTPβ-association occurred only during hyperglycemia. Disruption of vimetin/RPTPβ in diabetic mice inhibited RPTPβ polymerization, vimentin serine phosphorylation, and AKT activation in response to IGF-I, whereas nondiabetic mice showed no difference. The induction of vimentin phosphorylation is important for IGFBP-2-mediated enhancement of IGF-I-stimulated proliferation during hyperglycemia, and it

  14. Role of IGF-I signaling in muscle bone interactions.

    PubMed

    Bikle, Daniel D; Tahimic, Candice; Chang, Wenhan; Wang, Yongmei; Philippou, Anastassios; Barton, Elisabeth R

    2015-11-01

    Skeletal muscle and bone rely on a number of growth factors to undergo development, modulate growth, and maintain physiological strength. A major player in these actions is insulin-like growth factor I (IGF-I). However, because this growth factor can directly enhance muscle mass and bone density, it alters the state of the musculoskeletal system indirectly through mechanical crosstalk between these two organ systems. Thus, there are clearly synergistic actions of IGF-I that extend beyond the direct activity through its receptor. This review will cover the production and signaling of IGF-I as it pertains to muscle and bone, the chemical and mechanical influences that arise from IGF-I activity, and the potential for therapeutic strategies based on IGF-I. This article is part of a Special Issue entitled "Muscle Bone Interactions". PMID:26453498

  15. Pituitary and hypothalamic insulin-like growth factor-I (IGF-I) and IGF-I receptor expression in food-deprived rats.

    PubMed

    Olchovsky, D; Song, J; Gelato, M C; Sherwood, J; Spatola, E; Bruno, J F; Berelowitz, M

    1993-06-01

    The present study was designed to evaluate a possible role for the insulin-like growth factor-I (IGF-I) system in mediating the suppression of growth hormone (GH) secretion observed in food-deprived rats by measuring IGF-I mRNA, receptor concentration and receptor mRNA in neuroendocrine tissues (hypothalamus and pituitary). Rats were deprived of food (food-deprived) for 72 h or had free access to food (fed). Tissues were processed for measurement of steady-state levels of: (a) IGF-I and IGF-I receptor mRNA (by solution hybridization/RNase protection assay); (b) IGF-I in serum and tissue extracts (by RIA) and (c) IGF-I displaceable [125I]IGF-I binding to plasma membrane preparations. Food deprivation resulted in decreased serum and liver levels of IGF-I. Kidney IGF-I mRNA levels were reduced 80% in food-deprived rats with a concomitant increase in IGF-I receptor concentration and mRNA levels. Refeeding of food-deprived rats fully normalized these perturbations. Pituitary IGF-I content was reduced 50% in food-deprived rats while IGF-I mRNA levels were unaffected. A modest increase was seen in pituitary IGF-I receptor concentration; however, IGF-I receptor mRNA levels were not changed. Hypothalamic IGF-I mRNA content was reduced in 72 h food-deprived rats while IGF-I receptor binding capacity and mRNA were unaffected. In conclusion, IGF-I mRNA levels are decreased in liver, kidney and hypothalamus together with a reduction in plasma IGF-I in food-deprived rats but is unaffected in anterior pituitary. IGF-I receptor gene expression and binding capacity are coordinately regulated in kidney and hypothalamus, but not in the pituitary.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8349028

  16. Expression of insulin-like growth factors (IGFs), their receptors and IGF binding protein-3 in normal, benign and malignant smooth muscle tissues.

    PubMed Central

    Van der Ven, L. T.; Roholl, P. J.; Gloudemans, T.; Van Buul-Offers, S. C.; Welters, M. J.; Bladergroen, B. A.; Faber, J. A.; Sussenbach, J. S.; Den Otter, W.

    1997-01-01

    To assess the role of insulin-like growth factors (IGFs) in growth and transformation of normal (myometrium) and tumorous smooth muscle cell (SMC) tissues, in situ hybridization (ISH) analysis for insulin-like growth factor I and II (IGF-I and IGF-II) mRNAs was combined with detection of IGF peptides, their receptors and IGF binding protein-3 (IGFBP-3). mRNAs for both IGFs were detected in smooth muscle cells in normal, benign and malignant SMC tissues, together with the IGF peptides, both IGF receptors and IGFBP-3. This suggests an autocrine role for both IGFs. Leiomyomas had higher IGF-I peptide levels and higher levels of type I IGF receptors than myometrium, supporting the idea that IGFs play a role in the growth and transformation of these tumours. Low-grade leiomyosarcomas contained more IGF-II mRNAs than myometrium and leiomyoma, fewer type II IGF/mannose 6-phosphate receptors and less IGFBP-3 than myometrium and, in addition, fewer IGF-I mRNAs and type I IGF receptors than leiomyoma. Intermediate- and high-grade leiomyosarcomas had intermediate levels of IGF-II mRNAs and peptide, ranging between those in myometrium and low-grade leiomyosarcomas. Thus, growth and transformation of leiomyosarcomas may be regulated by IGF-II, although more markedly in low-grade than in high-grade leiomyosarcomas. In conclusion, the various categories of SMC tissues are associated with a distinct expression pattern of the IGF system. This suggests that each category of SMC tumours arises as a distinct entity and that there is no progression of transformation in these tissues. Images Figure 1 Figure 2 Figure 4 PMID:9184179

  17. The direct in vitro effect of insulin-like growth factors (IGFs) on normal bovine mammary cell proliferation and production of IGF binding proteins.

    PubMed

    McGrath, M F; Collier, R J; Clemmons, D R; Busby, W H; Sweeny, C A; Krivi, G G

    1991-08-01

    Mammary epithelial cells isolated from pregnant, nonlactating heifers were grown in vitro using collagen substrates. Using these systems, the truncated form of insulin growth factor-1 (IGF-1) (des-3-IGF-1), IGF-1, and IGF-2 all stimulated a significant (0.5 to 1 fold) increase in cell proliferation (des-3-IGF-1 greater than IGF-1 greater than IGF-2). When grown in media containing serum plus IGF-1, normal bovine mammary cells also produced and secreted at least four species of IGF-binding protein (IGFBP) ranging from 21K to 48K (as demonstrated by ligand blot analysis). However, cells grown in serum free media secreted detectable quantities of only 2 major forms of IGFBP of 34K and 48K. Using immunoblot analysis, these proteins were identified as IGFBP-2 and IGFBP-3, respectively. Both proteins were inducible by the addition of IGF to the serum free media (relative potency; IGF-1 greater than des-3-IGF-1 greater than IGF-2). Using RIA analysis, bovine mammary cells cultured in the presence of IGF-1 produced 20-25 ng/ml IGFBP-2 compared to control cultures which secrete approximately 1.0 ng/ml. Cells exposed to des-3-IGF-1 produced 40-60% less IGFBP-2 whereas insulin and IGF-2 did not stimulate significant IGFBP-2 production. These data indicate that normal bovine mammary cells secret IGFBP-2 and IGFBP-3. This secretion is stimulated by IGF-1 and des-3-IGF-1 suggesting a mechanism for regulating local IGF activity. PMID:1713160

  18. Somatotrope GHRH/GH/IGF-1 axis at the crossroads between immunosenescence and frailty.

    PubMed

    Bodart, Gwennaelle; Goffinet, Lindsay; Morrhaye, Gabriel; Farhat, Khalil; de Saint-Hubert, Marie; Debacq-Chainiaux, Florence; Swine, Christian; Geenen, Vincent; Martens, Henri J

    2015-09-01

    Immunosenescence, characterized by complex modifications of immunity with age, could be related to frailty syndrome in elderly individuals, leading to an inadequate response to minimal aggression. Functional decline (i.e., the loss of ability to perform activities of daily living) is related to frailty and decreased physiological reserves and is a frequent outcome of hospitalization in older patients. Links between immunosenescence and frailty have been explored and 20 immunological parameters, including insulin-like growth factor-1 (IGF-1), thymopoeisis, and telomere length, were shown to be affected in elderly patients with functional decline. A strong relationship between IGF-1 and thymic ouput was evidenced. IGF-1, a mediator of growth hormone (GH), was subsequently shown to induce interleukin-7 secretion in cultured primary human thymic epithelial cells. We are exploring the stress hypothesis in which an acute stressor is used as the discriminator of frailty susceptibility. GH can counteract the deleterious immunosuppressive effects of stress-induced steroids. Under nonstress conditions, the immunosenescent system preserves physiological responses, while under stress conditions, the combination of immunosenescence and a defect in the somatotrope axis might lead to functional decline. PMID:26284958

  19. The Effect of Skeletal Unloading on Bone Formation: Role of IGF-I

    NASA Technical Reports Server (NTRS)

    Bikle, D. D.; Kostenuik, P.; Holton, E. M.; Halloran, B. P.

    1999-01-01

    The best documented change in bone during space flight is the near cessation of bone formation. Space flight leads to a decrease in osteoblast number and activity, likely the result of altered differentiation of osteoblast precursors. The net result of these space flight induced changes is weaker bone. To understand the mechanism for these changes poses a challenge. Space flight studies must overcome enormous technical problems, and are necessarily limited in size and frequency. Therefore, ground based models have been developed to evaluate the effects of skeletal unloading. The hindlimb elevation (tail suspension) model simulates space flight better than other models because it reproduces the fluid shifts seen in space travel, is reversible, and is well tolerated by the animals with minimal evidence of stress as indicated by continued weight gain and normal levels and circadian rhythms of corticosterone. This is the model we have used for our experiments. Skeletal unloading by the hindlimb elevation method simulates a number of features of space flight in that bone formation, mineralization, and maturation are inhibited, osteoblast number is decreased, serum and skeletal osteocalcin levels fall, the ash content of bone decreases, and bone strength diminishes. We and others have shown that when osteoblasts or osteoprogenitor cells from the bones of the unloaded limbs are cultured in vitro they proliferate and differentiate more slowly, suggesting that skeletal unloading causes a persistent change in cell function which can be assessed in vitro. In contrast to the unweighted bones of the hindlimbs, no significant change in bone mass or bone formation is observed in the humeri, mandible, and cervical vertebrae during hindlimb elevation. The lack of effect of hindlimb elevation on bones like the humeri, mandible, and cervical vertebrae which are not unloaded by this procedure suggests that local factors rather than systemic effects dominate the response of bone to

  20. The impact of first trimester phthalate and phenol exposure on IGF2/H19 genomic imprinting and birth outcomes.

    PubMed

    LaRocca, Jessica; Binder, Alexandra M; McElrath, Thomas F; Michels, Karin B

    2014-08-01

    Genomic imprinting leads to parent-of-origin specific gene expression and is determined by epigenetic modification of genes. The paternally expressed gene insulin-like growth-factor 2 (IGF2) is located about ~100kb from the maternally expressed non-coding gene H19 on human chromosome 11, and both genes play major roles in embryonic and placental growth. Given adverse gestational environments can influence DNA methylation patterns in extra-embryonic tissues, we hypothesized that prenatal exposure to endocrine disrupting chemicals (EDCs) alters H19 and IGF2 methylation in placenta. Our study was restricted to a total of 196 women co-enrolled in the Predictors of Preeclampsia Study and the Harvard Epigenetic Birth Cohort. First trimester urine concentrations of 8 phenols and 11 phthalate metabolites were measured and used to characterize EDC exposure profiles. We assessed methylation of differentially methylated regions (DMRs) by pyrosequencing of H19, IGF2DMR0, and IGF2DMR2 and correlated values with phenol and phthalate metabolites. We also assessed overall expression and allele-specific expression of H19 and IGF2. We found several significant associations between DNA methylation and additive biomarker measurements. A significant decrease in H19 methylation was associated with high levels of the sum (Σ) of phthalate metabolites and metabolites of low molecular weight (LMW) phthalates. Σphthalate and LMW phthalate concentrations were inversely associated with IGF2DMR0 methylation values. Variation in methylation was not associated with changes in allele-specific expression. However increased deviation of allele-specific expression of H19 was associated with Σdi(2-ethylhexyl) phthalate metabolites and high molecular weight phthalates. Neither methylation nor expression of these imprinted regions had a significant impact on birth length or birth weight. Overall, our study provides new insight into an epigenetic mechanism that occurs following EDC exposure. PMID

  1. The Impact of First Trimester Phthalate and Phenol Exposure on IGF2/H19 Genomic Imprinting and Birth Outcomes

    PubMed Central

    LaRocca, Jessica; Binder, Alexandra; McElrath, Thomas F.; Michels, Karin B.

    2014-01-01

    Genomic imprinting leads to parent-of-origin specific gene expression and is determined by epigenetic modification of genes. The paternally expressed gene insulin-like growth-factor 2 (IGF2) is located about ∼100 kb from the maternally expressed non-coding gene H19 on human chromosome 11, and both genes play major roles in embryonic and placental growth. Given adverse gestational environments can influence DNA methylation patterns in extra-embryonic tissues, we hypothesized that prenatal exposure to endocrine disrupting chemicals (EDCs) alters H19 and IGF2 methylation in placenta. Our study was restricted to a total of 196 women co-enrolled in the Predictors of Preeclampsia Study and the Harvard Epigenetic Birth Cohort. First trimester urine concentrations of 8 phenols and 11 phthalate metabolites were measured and used to characterize EDC exposure profiles. We assessed methylation of differentially methylated regions (DMRs) by pyrosequencing of H19, IGF2DMR0, and IGF2DMR2 and correlated values with phenol and phthalate metabolites. We also assessed overall expression and allele-specific expression of H19 and IGF2. We found several significant associations between DNA methylation and additive biomarker measurements. A significant decrease in H19 methylation was associated with high level of the sum (Σ) of phthalate metabolites and metabolites of low molecular weight (LMW) phthalates. Σphthalate and LMW phthalate concentrations were inversely associated with IGF2DMR0 methylation values. Variation in methylation was not associated with changes in allele-specific expression. However increased deviation of allele-specific expression of H19 was associated with Σ di(2-ethylhexyl) phthalate metabolites and high molecular weight phthalates. Neither methylation nor expression of these imprinted regions had a significant impact on birth length or birth weight. Overall, our study provides new insight into an epigenetic mechanism that occurs following EDC exposure. PMID

  2. Role of IGF-1 pathway in lung fibroblast activation

    PubMed Central

    2013-01-01

    Background IGF-1 is elevated in pulmonary fibrosis and acute lung injury, where fibroblast activation is a prominent feature. We previously demonstrated that blockade of IGF pathway in murine model of lung fibrosis improved outcome and decreased fibrosis. We now expand that study to examine effects of IGF pathway on lung fibroblast behaviors that could contribute to fibrosis. Methods We first examined mice that express αSMA promoter upstream of GFP reporter treated with A12, a blocking antibody to IGF-1 receptor, after bleomycin induced lung injury. We then examined the effect of IGF-1 alone, or in combination with the pro-fibrotic cytokine TGFβ on expression of markers of myofibroblast activation in vitro, including αSMA, collagen α1, type 1, collagen α1, type III, and TGFβ expression. Results After bleomycin injury, we found decreased number of αSMA-GFP + cells in A12 treated mice, validated by αSMA immunofluorescent staining. We found that IGF-1, alone or in combination with TGF-β, did not affect αSMA RNA expression, promoter activity, or protein levels when fibroblasts were cultured on stiff substrate. IGF-1 stimulated Col1a1 and Col3a1 expression on stiff substrate. In contrast, IGF-1 treatment on soft substrate resulted in upregulation of αSMA gene and protein expression, as well as Col1a1 and Col3a1 transcripts. In conclusion, IGF-1 stimulates differentiation of fibroblasts into a myofibroblast phenotype in a soft matrix environment and has a modest effect on αSMA stress fiber organization in mouse lung fibroblasts. PMID:24103846

  3. Transcriptional regulation of IGF-I expression in skeletal muscle

    NASA Technical Reports Server (NTRS)

    McCall, G. E.; Allen, D. L.; Haddad, F.; Baldwin, K. M.

    2003-01-01

    The present study investigated the role of transcription in the regulation of insulin-like growth factor (IGF)-I expression in skeletal muscle. RT-PCR was used to determine endogenous expression of IGF-I pre-mRNA and mRNA in control (Con) and functionally overloaded (FO) rat plantaris. The transcriptional activities of five different-length IGF-I promoter fragments controlling transcription of a firefly luciferase (FLuc) reporter gene were tested in vitro by transfection of myoblasts or in vivo during FO by direct gene transfer into the plantaris. Increased endogenous IGF-I gene transcription during 7 days of plantaris FO was evidenced by an approximately 140-160% increase (P < 0.0001) in IGF-I pre-mRNA (a transcriptional marker). IGF-I mRNA expression also increased by approximately 90% (P < 0.0001), and it was correlated (R = 0.93; P < 0.0001) with the pre-mRNA increases. The three longest IGF-I exon 1 promoters induced reporter gene expression in proliferating C2C12 and L6E9 myoblasts. In differentiated L6E9 myotubes, promoter activity increased approximately two- to threefold over myoblasts. Overexpression of calcineurin and MyoD increased the activity of the -852/+192 promoter in C2C12 myotubes by approximately 5- and approximately 18-fold, respectively. However, FO did not induce these exogenous promoter fragments. Nevertheless, the present findings are consistent with the hypothesis that the IGF-I gene is transcriptionally regulated during muscle hypertrophy in vivo as evidenced by the induction of the endogenous IGF-I pre-mRNA during plantaris FO. The exon 1 promoter region of the IGF-I gene is sufficient to direct inducible expression in vitro; however, an in vivo response to FO may require elements outside the -852/+346 region of the exon 1 IGF-I promoter or features inherent to the endogenous IGF-I gene.

  4. Effect of recombinant porcine IGFBP-3 on IGF-I and long-R3-IGF-I-stimulated proliferation and differentiation of L6 myogenic cells.

    PubMed

    Xi, G; Kamanga-Sollo, E; Pampusch, M S; White, M E; Hathaway, M R; Dayton, William R

    2004-09-01

    Insulin-like growth factor (IGF)-I stimulates both proliferation and differentiation of myogenic precursor cells. In vivo, IGFs are bound to one of the members of a family of six high-affinity IGF binding proteins (IGFBP 1-6) that regulate their biological activity. One of these binding proteins, IGFBP-3, affects cell proliferation via both IGF-dependent and IGF-independent mechanisms and it has generally been shown to suppress proliferation of cultured cells; however, it also may stimulate proliferation depending upon the cell type and the assay conditions. Cultured porcine embryonic myogenic cells (PEMCs) produce IGFBP-3 and its level drops significantly immediately prior to differentiation. Additionally, IGFBP-3 suppresses both IGF-I and Long-R3-IGF-I-stimulated proliferation of embryonic porcine myogenic cells. In this study, we have examined the effects of recombinant porcine IGFBP-3 (rpIGFBP-3) on IGF-I- and Long-R3-IGF-I-stimulated proliferation and differentiation of the L6 myogenic cell line. L6 cells potentially provide a good model for studying the actions of IGFBP-3 on muscle because they contain no non-muscle cells and they do not produce detectable levels of IGFBP-3. RpIGFBP-3 suppresses both IGF-I and Long-R3-IGF-I-stimulated proliferation of L6 cells, indicating that it suppresses proliferation via both IGF-dependent and IGF-independent mechanisms. Our data also show that rpIGFBP-3 causes IGF-independent suppression of proliferation without increasing the level of phosphosmad-2 in L6 cultures. Additionally, rpIGFBP-3 suppresses IGF-I-stimulated differentiation of L6 cells. In contrast, however, rpIGFBP-3 does not suppress Long-R3-IGF-I-stimulated differentiation. This suggests that rpIGFBP-3 does not have IGF-independent effects on L6 cell differentiation. PMID:15254966

  5. Effect of IGFBP-3 on IGF- and IGF-analogue-induced insulin-like growth factor-I receptor (IGFIR) signalling.

    PubMed

    Devi, G R; Graham, D L; Oh, Y; Rosenfeld, R G

    2001-08-01

    Insulin-like growth factor binding protein-3 (IGFBP-3) binds IGF-I and IGF-II with high affinity, at least an order of magnitude higher than the affiniy of the IGFs for the IGFIR. It has been hypothesized that IGFBP-3 inhibits IGF binding to the IGFIR via a mechanism independent of its ability to sequester IGFs. In the present study, we examined the effects of IGFBP-3 and its proteolytic fragments on the initial events of the IGFIR signalling pathway. IGFBP-3 inhibited IGF-I-, IGF-II-, Des(1-3)IGF-I- and Long(R3)IGF-I-induced IGFIR phosphorylation in a dose-dependent manner at similar concentration range but not QAYL-induced IGFIR-P. The((1-97))IGFBP-3 fragment was able to inhibit only IGF-I-induced IGFIR-P. The((1-97))IGFBP-3 fragment but not intact IGFBP-3 inhibited insulin-induced IGFIR-P. Monolayer cross-linking with [(125)I]IGFBP-3 indicated that there is no direct interaction of IGFBP-3 with the IGFIR. This study demonstrates that the effect on the initial step of IGFIR signalling by IGFBP-3 is largely due to its ability to sequester IGF and the IGF analogues in the extracellular milieu and not the result of any interaction of IGFBP-3 with the IGFIR or a mechanism independent of its ability to bind IGFs. PMID:11735239

  6. IGF-2/IGF-1R signaling has distinct effects on Sox1, Irx3, and Six3 expressions during ES cell derived-neuroectoderm development in vitro.

    PubMed

    Takata, Nozomu; Sakakura, Eriko; Sasai, Yoshiki

    2016-05-01

    Insulin-like growth factors (IGFs) are involved in growth and tissue development, including diseases such as type-2 diabetes and cancers. However, their roles in lineage specification, especially in early mammalian neural development, are poorly understood. Here, we analyzed the protein expression of IGF-2 in early mouse embryo, and it was preferentially detected in anterior mesodermal tissue, adjacent to the neural plate. We utilized a self-organizing neural tissue culture system and analyzed the direct effect of IGF-2 on the general neural marker Sox1. Interestingly, using recombinant IGF-2 and a chemical inhibitor of its receptor (IGF-1R), we found that the IGF-2/IGF-1R pathway positively regulated Sox1 expression in embryonic stem (ES) cell-derived neural tissue. Furthermore, to visualize the expression patterns of other neural markers, we used reporter ES cell lines and we found that the IGF-2/IGF-1R signaling upregulated the expression of the posterior neural marker Irx3. In contrast, the anterior neural marker Six3 was downregulated by IGF-2/IGF-1R signaling. Together, our results demonstrate that IGF-2/IGF-1R signaling has different effects on neural marker expression, which may influence the early regional identity of ES cell-derived neural tissues. PMID:26956358

  7. Isolation of an inhibitory insulin-like growth factor (IGF) binding protein from bone cell-conditioned medium: A potential local regulator of IGF action

    SciTech Connect

    Mohan, S.; Bautista, C.M.; Wergedal, J.; Baylink, D.J. )

    1989-11-01

    Inhibitory insulin-like growth factor binding protein (In-IGF-BP) has been purified to homogeneity from medium conditioned by TE89 human osteosarcoma cells by two different methods using Sephadex G-100 gel filtration, FPLC Mono Q ion-exchange, HPLC C{sub 4} reverse-phase, HPLC CN reverse-phase and affinity chromatographies. In-IGF-BP thus purified appeared to be homogeneous and unique by the following criteria. (i) N-terminal sequence analysis yielded a unique sequence (Asp-Glu-Ala-Ile-His-Cys-Pro-Pro-Glu-Ser-Glu-Ala-Lys-Leu-Ala). (ii) Amino acid composition of In-IGF-BP revealed marked differences with the amino acid compositions of other known PBs. (iii) In-IGF-BP exhibited a single band with molecular mass of 25 kDa under reducing conditions on sodium dodecyl sulfate/polyacrylamide gels. IGF-I and IGF-II but not insulin displaced the binding of {sup 125}I-labeled IGF-I or {sup 125}I-labeled IGF-II binding to In-IGF-BP. In-IGF-BP inhibited basal, IGF-stimulated bone cell proliferation and serum-stimulated bone cell proliferation. Forskolin increases synthesis of In-IGF-BP in TE85 human osteosarcoma cells in a dose-dependent manner. Based on these findings, the authors conclude that In-IGF-BP is a protein that has a unique sequence and significant biological actions on bone cells.

  8. Repression of Igf1 expression by Ezh2 prevents basal cell differentiation in the developing lung.

    PubMed

    Galvis, Laura A; Holik, Aliaksei Z; Short, Kieran M; Pasquet, Julie; Lun, Aaron T L; Blewitt, Marnie E; Smyth, Ian M; Ritchie, Matthew E; Asselin-Labat, Marie-Liesse

    2015-04-15

    Epigenetic mechanisms involved in the establishment of lung epithelial cell lineage identities during development are largely unknown. Here, we explored the role of the histone methyltransferase Ezh2 during lung lineage determination. Loss of Ezh2 in the lung epithelium leads to defective lung formation and perinatal mortality. We show that Ezh2 is crucial for airway lineage specification and alveolarization. Using optical projection tomography imaging, we found that branching morphogenesis is affected in Ezh2 conditional knockout mice and the remaining bronchioles are abnormal, lacking terminally differentiated secretory club cells. Remarkably, RNA-seq analysis revealed the upregulation of basal genes in Ezh2-deficient epithelium. Three-dimensional imaging for keratin 5 further showed the unexpected presence of a layer of basal cells from the proximal airways to the distal bronchioles in E16.5 embryos. ChIP-seq analysis indicated the presence of Ezh2-mediated repressive marks on the genomic loci of some but not all basal genes, suggesting an indirect mechanism of action of Ezh2. We found that loss of Ezh2 de-represses insulin-like growth factor 1 (Igf1) expression and that modulation of IGF1 signaling ex vivo in wild-type lungs could induce basal cell differentiation. Altogether, our work reveals an unexpected role for Ezh2 in controlling basal cell fate determination in the embryonic lung endoderm, mediated in part by repression of Igf1 expression. PMID:25790853

  9. Expression and functional characterization of intrafollicular GH-IGF system in the zebrafish ovary.

    PubMed

    Zhou, Rui; Yu, Susana Man Ying; Ge, Wei

    2016-06-01

    The somatotrophic axis plays important roles in influencing reproduction. All key members of this axis including growth hormone (GH, gh), GH receptors (ghra and ghrb), insulin-like growth factors (IGFs, igf1, igf2 and igf3) and IGF receptors (igf1ra and igf1rb) were detected in the zebrafish ovary. GH was exclusively expressed in the full-grown oocytes, while its receptors were detectable in both the follicle cells and oocytes. The IGFs and their receptors were all expressed in both compartments except igf3, which was expressed in the follicle cells only. During folliculogenesis, there was a sharp decrease of gh expression at follicle activation; however, the expression of its receptors increased significantly. The expression profiles of igf1, igf2a, and igf2b were similar to that of fshr, whereas igf3 expression was close to lhcgr, suggesting differential roles for different forms of IGFs in follicle development. To examine if the ovarian GH-IGF system is regulated by gonadotropins (e.g., hCG) and GH, we performed in vitro experiments using cultured zebrafish follicle cells. The expression of igf1 and igf1ra, but not others, was down-regulated by hCG (LH analog), whereas recombinant zebrafish GH stimulated igf1 expression. In addition, GH also increased the expression of activin βA subunit (inhbaa). In agreement with this, the stimulatory effect of GH but not IGF-I on oocyte maturation could be abolished by follistatin. In conclusion, the present study revealed an intrafollicular network involving GH-IGF mini-axis in the zebrafish ovary; however, it might not work in the same way as that of the systemic somatotrophic axis. PMID:26654745

  10. Differential regulation of IGF-binding proteins in rabbit costal chondrocytes by IGF-I and dexamethasone.

    PubMed

    Koedam, J A; Hoogerbrugge, C M; Van Buul-Offers, S C

    2000-06-01

    Cartilage is a primary target tissue for the IGFs. The mitogenic activity of these peptides is regulated by a family of high-affinity IGF-binding proteins (IGFBP-1 to -6). We characterized the IGFBPs produced by cultured chondrocytes derived from rib cartilage of prepubertal rabbits. Culture medium, which had been conditioned by these cells for 48 h showed bands of 22 kDa, 24 kDa and a 31/32 kDa doublet by Western ligand blotting with [(125)I]IGF-II. When the cells were grown in the presence of increasing amounts of IGF-I or IGF-II, the 31/32 kDa doublet increased in intensity (reaching a plateau of about 11-fold stimulation between 2 and 10 nM IGF-I). The 22 kDa and 24 kDa bands increased only slightly while a 26 kDa band became faintly visible. By Western immunoblotting the 31/32 kDa doublet was identified as IGFBP-5. An IGF-I analog with reduced affinity for IGFBPs, Long-R3 IGF-I, also induced IGFBP-5, while insulin was less effective (2.2-fold stimulation at 10 nM). IGF-I protected IGFBP-5 against proteolytic degradation by conditioned medium. IGF-I also enhanced the level of IGFBP-5 mRNA. LY294002, a specific inhibitor of the intracellular signaling molecule phosphatidylinositol 3-kinase, inhibited stimulation of IGFBP-5 by IGF-I. Dexamethasone suppressed IGFBP-5 (by 70% at 20 nM) but, at the same time, a 39/41 kDa doublet (presumably IGFBP-3) was induced. IGFBP-5 has been shown in several cell types to enhance the mitogenic activity of IGF-I. IGFBP-3 generally acts as a growth inhibitor. Therefore, the differential effects of dexamethasone on these regulatory proteins could account, at least in part, for the growth-arresting effect of this glucocorticoid. PMID:10828839

  11. Insulin-like growth factor-I (IGF-I) and especially IGF-I variants are anabolic in dexamethasone-treated rats.

    PubMed

    Tomas, F M; Knowles, S E; Owens, P C; Chandler, C S; Francis, G L; Read, L C; Ballard, F J

    1992-02-15

    The administration of insulin-like growth factor-I (IGF-I) via subcutaneously implanted osmotic pumps partially reversed a catabolic state produced by the co-administration of 20 micrograms of dexamethasone/day to 150 g male rats. Marked dose-dependent effects on body weight and nitrogen retention were produced, with the highest IGF-I dose, 695 micrograms/day, giving a 6 g increase in body weight over 7 days, compared with a 19 g loss in the dexamethasone-only group and an 18 g gain in pair-fed controls. Two IGF-I analogues that bind poorly to IGF-binding proteins, the truncated form, des(1-3)IGF-I, and a variant with an N-terminal extension as well as arginine at residue 3, LR3IGF-I, were approx. 2.5-fold more potent than IGF-I. The response with LR3IGF-I was particularly striking because this peptide binds 3-fold less well than IGF-I to the type 1 IGF receptor. The increased potencies of the IGF-I variants may relate to the substantially increased plasma levels of IGF-binding proteins, particularly IGFBP-3, produced by the combined treatment of dexamethasone with IGF-I or the variants. These binding proteins would be expected to decrease the transfer of IGF-I, but not that of the variants, from blood to tissue sites of action. Measurements of muscle protein synthesis at the end of the treatment period and muscle protein breakdown by 3-methylhistidine (3MH) excretion throughout the experiment indicated coordinate anabolic effects of the IGF peptides on both processes. Thus 3MH excretion was decreased at the highest IGF-I dose from 83.5 +/- 4.2 (S.E.M.) mumol/kg per 7 days to 65.1 +/- 2.2, compared with 54.9 +/- 1.2 in the pair-fed controls. Part of this response in 3MH excretion may have reflected a decrease in gut protein breakdown, because IGF-I and especially the IGF analogues increased the gut weight by up to 45%. Notwithstanding the effects on protein synthesis and breakdown, the fractional carcass weights remained low in the IGF-treated groups, although the

  12. Insulin-like growth factor (IGF) binding protein from human decidua inhibits the binding and biological action of IGF-I in cultured choriocarcinoma cells

    SciTech Connect

    Ritvos, O.; Ranta, T.; Jalkanen, J.; Suikkari, A.M.; Voutilainen, R.; Bohn, H.; Rutanen, E.M.

    1988-05-01

    The placenta expresses genes for insulin-like growth factors (IGFs) and possesses IGF-receptors, suggesting that placental growth is regulated by IGFs in an autocrine manner. We have previously shown that human decidua, but not placenta, synthesizes and secretes a 34 K IGF-binding protein (34 K IGF-BP) called placental protein 12. We now used human choriocarcinoma JEG-3 cell monolayer cultures and recombinant (Thr59)IGF-I as a model to study whether the decidual 34 K IGF-BP is able to modulate the receptor binding and biological activity of IGFs in trophoblasts. JEG-3 cells, which possess type I IGF receptors, were unable to produce IGF-BPs. Purified 34 K IGF-BP specifically bound (125I)iodo-(Thr59)IGF-I. Multiplication-stimulating activity had 2.5% the potency of (Thr59)IGF-I, and insulin had no effect on the binding of (125I) iodo-(Thr59)IGF-I. 34 K IGF-BP inhibited the binding of (125I) iodo-(Thr59)IGF-I to JEG-3 monolayers in a concentration-dependent manner by forming with the tracer a soluble complex that could not bind to the cell surface as demonstrated by competitive binding and cross-linking experiments. After incubating the cell monolayers with (125I)iodo-(Thr59)IGF-I in the presence of purified binding protein, followed by cross-linking, no affinity labeled bands were seen on autoradiography. In contrast, an intensely labeled band at 40 K was detected when the incubation medium was analyzed, suggesting that (Thr59)IGF-I and 34 K IGF-BP formed a complex in a 1:1 molar ratio. Also, 34 K IGF-BP inhibited both basal and IGF-I-stimulated uptake of alpha-(3H)aminoisobutyric acid in JEG-3 cells. RNA analysis revealed that IGF-II is expressed in JEG-3 cells.

  13. Proteolytic degradation of insulin-like growth factor (IGF)-binding protein-3 by porcine ovarian granulosa cells in culture: regulation by IGF-I.

    PubMed

    Grimes, R W; Hammond, J M

    1994-01-01

    Porcine ovarian granulosa cells in culture secrete glycosylated insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3), which inhibits gonadotropin and IGF action in the ovary. Synthesis of IGFBP-3 is stimulated by IGF-I and attenuated by gonadotropin. The purpose of the present study was to determine whether IGFBP-3 levels were also regulated via proteolysis. Exogenously added nonglycosylated recombinant human IGFBP-3 (rhIGFBP-3) was significantly degraded over time by a soluble serine-specific protease, similar to plasmin, in control cultures and those treated with FSH, insulin, or several other classes of hormones. In contrast, degradation was greatly attenuated by the IGFs. Degraded rhIGFBP-3 exhibited much reduced affinity for [125I]IGF-II, suggesting that degradation could make available IGFs for cellular interaction. The mechanism of IGFBP-3 protease inhibition by IGFs is unclear. Mediation by IGF receptors is unlikely, as insulin at a dose that activated both insulin and type I IGF receptors did not alter intrinsic degradation of IGFBP-3 (as does IGF). Additionally, IGF-I attenuation of IGFBP-3 degradation was not inhibited by antagonism of receptor action with a tyrosine kinase inhibitor. Further, IGF-I inhibited degradation in cell-free conditioned medium. Direct stabilization of IGFBP-3 via binding of IGFs was suggested from these results. However, long R3 IGF-I attenuated IGFBP-3 degradation even though it has low affinity for IGFBPs. Inhibition of the protease by IGFs is also possible. We conclude that IGFs inhibit the degradation of exogenous nonglycosylated rhIGFBP-3. If active in vivo, this may serve to increase endogenous IGFBP-3 levels in follicular fluid. PMID:7506209

  14. Effects of selection for blood serum IGF-I concentration on reproductive performance of female Angus beef cattle.

    PubMed

    Zhang, X; Davis, M E; Moeller, S J; Ottobre, J S

    2013-09-01

    Reproductive performance of animals affects lifetime productivity. However, improvement of reproductive traits via direct selection is generally slow due to low heritability. Therefore, identification of indicator traits for reproductive performance may enhance genetic response. Previous studies showed that serum IGF-I concentration is a candidate indicator for growth and reproductive traits. The objective of our study was to estimate the variances or covariances of IGF-I concentration with reproductive traits. Data were collected from a divergent selection experiment for serum IGF-I concentration at the Eastern Agricultural Research Station owned by The Ohio State University. The study included a total of 2,662 calves in the 1989 to 2005 calf crops. Variance or covariance components were estimated for direct and maternal genetic effects, maternal environment effects, environment effects, and phenotypic effects using an animal model in a multiple-trait, derivative-free, restricted maximum likelihood (MTDFREML, Boldman et al., 1995) computer program. Direct additive genetic correlations suggest that selection for greater IGF-I concentration (heritability = 0.50 ± 0.07) could lead to increased conception rate (heritability = 0.11 ± 0.06, r = 0.32, P < 0.001) and calving rate (heritability = 0.13 ± 0.06, r = 0.43, P < 0.001) and decreased age at first calving in heifers (heritability = 0.35 ± 0.20, r = -0.40, P < 0.001). PMID:23894000

  15. [The developmental patterns of GH-R, IGF-1 and IGF-IR gene expression in sheep skin].

    PubMed

    Jia, Bin; Xi, Ji-Feng; Zhang, Su-Yun; Zhao, Zong-Sheng; Zhao, Ru-Qian; Chen, Jie

    2006-09-01

    Semi-quantitative RT-PCR was applied to investigate the developmental patterns of GH-R, IGF-1 and IGF-IR mRNA expression in skin of two sheep breeds. One breed was the first filial generation (F1) of Romilly Hillys x Merino of China (Xinjiang Agricultural Reclamation line) wool sheep, and the other was Kazak hair sheep. 18S rRNA was used as the internal standard. Sheep were weighed and wool and skin samples were collected at different times. Results showed that body weight increased rapidly during 30-135 days but slowed during 135-255 days. Wool growth increased gradually during 30-135 days, degreased till 180 days of age, but rebounded thereafter. Overall, body weight and developmental patterns of wool growth was not significant different between hair and wool sheep. GH-R mRNA expression in the skin of hair sheep increased significantly during 30-90 days, peaked at 90 days of age (P<0.05), then declined signifi cantly (P<0.05). GH-R mRNA expression in the skin of wool sheep increased significantly until 135 days of age (P<0.01) and then decreased significantly (P<0.01). The peak level was higher in the wool sheep than the hair sheep. The expression of cantly IGF-1 mRNA and IGF-IR mRNA in the skin of hair sheep increased during 30-90 days, then declined significantly (P<0.01). The expression of IGF-1 mRNA and IGF-IR mRNA in the skin of wool sheep were high at birth and then reduced gradually. The IGF-1 mRNA expression in the skin of hair sheep reached its peak at 90 days of age, and was significant higher than that of wool sheep. The expression of GH-R, IGF-1 and IGF-IR mRNA in skin of hair sheep was higher than that of wool sheep before 90 days of age, but was lower after that. The results suggest that GH-R, IGF-1 and IGF-IR mRNA expression in the skin of sheep follows specific developmental patterns, and different patterns exist between the two breeds. PMID:16963415

  16. The Insulin/IGF System in Colorectal Cancer Development and Resistance to Therapy

    PubMed Central

    Vigneri, Paolo Giovanni; Tirrò, Elena; Pennisi, Maria Stella; Massimino, Michele; Stella, Stefania; Romano, Chiara; Manzella, Livia

    2015-01-01

    The insulin/insulin-like growth factor (IGF) system is a major determinant in the pathogenesis and progression of colorectal cancer (CRC). Indeed, several components of this signaling network, including insulin, IGF-1, IGF-2, the IGF-binding proteins, the insulin receptor (IR), the IGF-1 receptor (IGF-1R), and IR substrate proteins 1 and 2 contribute to the transformation of normal colon epithelial cells. Moreover, the insulin/IGF system is also implicated in the development of resistance to both chemotherapeutic drugs and epidermal growth factor receptor targeted agents. The identification of hybrid receptors comprising both the IR and IGF-1R adds further complexity to this signaling network. Thus, a comprehensive understanding of the biological functions performed by each component of the insulin/IGF system is required to design successful drugs for the treatment of CRC patients. PMID:26528439

  17. IGF-1R as an anti-cancer target—trials and tribulations

    PubMed Central

    Chen, Helen X.; Sharon, Elad

    2013-01-01

    Type I insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/IGF-1R inhibitors have entered clinical trials, and these belong to three main classes: (1) monoclonal antibodies against IGF-1R, (2) monoclonal antibodies against IGF-1R ligands (IGF-1 and IGF-2), and (3) IGF-1R tyrosine kinase inhibitors. These IGF-1R–targeting agents share common effects on IGF-1R signaling but differ in mechanisms of action, spectrum of target inhibition, and pharmacological features. Clinical activity of IGF-1R inhibitors has been demonstrated with sustained responses in a small number of patients with select tumor types, such as Ewing sarcoma and thymoma. However, many large clinical trials involving patients with adult tumors, including non–small cell lung cancer, breast cancer, and pancreatic cancer, failed to show clinical benefit in the overall patient population. Possible reasons for failure include the complexity of the IGF-1R/insulin receptor system and parallel growth and survival pathways, as well as a lack of patient selection markers. While IGF-1R remains a valid target for selected tumor types, identification of predictive markers and rational combinations will be critical to success in future development. PMID:23601239

  18. STRONG EXPRESSION OF IGF1R IN PEDIATRIC GASTROINTESTINAL STROMAL TUMORS WITHOUT IGF1R GENOMIC AMPLIFICATION

    PubMed Central

    Janeway, Katherine A.; Zhu, Mei-Jun; Barretina, Jordi; Perez-Atayde, Antonio; Demetri, George D.; Fletcher, Jonathan A.

    2010-01-01

    Wildtype (WT) gastrointestinal stromal tumors (GISTs), lacking mutations in KIT or PDGFRA, represent 85% of GISTs in pediatric patients. Treatment options for pediatric WT GIST are limited. Recently, expression profiling of a limited number of pediatric and adult WT GISTs and more in depth study of a single pediatric WT GIST implicated the insulin like growth factor 1 receptor (IGF1R) as a potential therapeutic target in pediatric WT GIST. We performed immunoblotting, SNP and FISH studies to determine the extent of expression, biochemical activation and genomic amplification of IGF1R in a larger number of pediatric WT GISTs. Pediatric WT GISTs expressed IGF1R strongly, whereas typical adult KIT mutant GISTs did not. IGF1R gene amplification was not detected in pediatric WT GISTs, and some KIT-mutant GISTs had IGF1R gene deletion due to monosomy 15. Despite the absence of apparent genomic activation mechanisms accounting for overexpression, clinical study of IGF1R-directed therapies in pediatric WT GIST is warranted. PMID:20162573

  19. c-myb stimulates cell growth by regulation of insulin-like growth factor (IGF) and IGF-binding protein-3 in K562 leukemia cells

    SciTech Connect

    Kim, Min-Sun; Kim, Sun-Young; Arunachalam, Sankarganesh; Hwang, Pyoung-Han; Yi, Ho-Keun; Nam, Sang-Yun; Lee, Dae-Yeol

    2009-07-17

    c-myb plays an important role in the regulation of cell growth and differentiation, and is highly expressed in immature hematopoietic cells. The human chronic myelogenous leukemia cell K562, highly expresses IGF-I, IGF-II, IGF-IR, and IGF-induced cellular proliferation is mediated by IGF-IR. To characterize the impact of c-myb on the IGF-IGFBP-3 axis in leukemia cells, we overexpressed c-myb using an adenovirus gene transfer system in K562 cells. The overexpression of c-myb induced cell proliferation, compared to control, and c-myb induced cell growth was inhibited by anti-IGF-IR antibodies. c-myb overexpression resulted in a significant increase in the expression of IGF-I, IGF-II, and IGF-IR, and a decrease in IGFBP-3 expression. By contrast, disruption of c-myb function by DN-myb overexpression resulted in significant reduction of IGF-I, IGF-II, IGF-IR, and elevation of IGFBP-3 expression. In addition, exogenous IGFBP-3 inhibited the proliferation of K562 cells, and c-myb induced cell growth was blocked by IGFBP-3 overexpression in a dose-dependent manner. The growth-promoting effects of c-myb were mediated through two major intracellular signaling pathways, Akt and Erk. Activation of Akt and Erk by c-myb was completely blocked by IGF-IR and IGFBP-3 antibodies. These findings suggest that c-myb stimulates cell growth, in part, by regulating expression of the components of IGF-IGFBP axis in K562 cells. In addition, disruption of c-myb function by DN-myb may provide a useful strategy for treatment of leukemia.

  20. Insulin growth factor-1 (IGF-1) enhances hippocampal excitatory and seizure activity through IGF-1 receptor-mediated mechanisms in the epileptic brain.

    PubMed

    Jiang, Guohui; Wang, Wei; Cao, Qingqing; Gu, Juan; Mi, Xiujuan; Wang, Kewei; Chen, Guojun; Wang, Xuefeng

    2015-12-01

    Insulin-like growth factor-1 (IGF-1) is known to promote neurogenesis and survival. However, recent studies have suggested that IGF-1 regulates neuronal firing and excitatory neurotransmission. In the present study, focusing on temporal lobe epilepsy, we found that IGF-1 levels and IGF-1 receptor activation are increased in human epileptogenic tissues, and pilocarpine- and pentylenetetrazole-treated rat models. Using an acute model of seizures, we showed that lateral cerebroventricular infusion of IGF-1 elevates IGF-1 receptor (IGF-1R) signalling before pilocarpine application had proconvulsant effects. In vivo electroencephalogram recordings and power spectrogram analysis of local field potential revealed that IGF-1 promotes epileptiform activities. This effect is diminished by co-application of an IGF-1R inhibitor. In an in vitro electrophysiological study, we demonstrated that IGF-1 enhancement of excitatory neurotransmission and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor- and N-methyl-D-aspartate receptor-mediated currents is inhibited by IGF-1R inhibitor. Finally, activation of extracellular signal-related kinase (ERK)-1/2 and protein kinase B (Akt) in seizures in rats is increased by exogenous IGF-1 and diminished by picropodophyllin. A behavioural study reveals that the ERK1/2 or Akt inhibitor attenuates seizure activity. These results indicate that increased IGF-1 levels after recurrent hippocampal neuronal firings might, in turn, promote seizure activity via IGF-1R-dependent mechanisms. The present study presents a previously unappreciated role of IGF-1R in the development of seizure activity. PMID:26286172

  1. Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer

    PubMed Central

    Archetti, Marco; Ferraro, Daniela A.; Christofori, Gerhard

    2015-01-01

    The extensive intratumor heterogeneity revealed by sequencing cancer genomes is an essential determinant of tumor progression, diagnosis, and treatment. What maintains heterogeneity remains an open question because competition within a tumor leads to a strong selection for the fittest subclone. Cancer cells also cooperate by sharing molecules with paracrine effects, such as growth factors, and heterogeneity can be maintained if subclones depend on each other for survival. Without strict interdependence between subclones, however, nonproducer cells can free-ride on the growth factors produced by neighboring producer cells, a collective action problem known in game theory as the “tragedy of the commons,” which has been observed in microbial cell populations. Here, we report that similar dynamics occur in cancer cell populations. Neuroendocrine pancreatic cancer (insulinoma) cells that do not produce insulin-like growth factor II (IGF-II) grow slowly in pure cultures but have a proliferation advantage in mixed cultures, where they can use the IGF-II provided by producer cells. We show that, as predicted by evolutionary game theory, producer cells do not go extinct because IGF-II acts as a nonlinear public good, creating negative frequency-dependent selection that leads to a stable coexistence of the two cell types. Intratumor cell heterogeneity can therefore be maintained even without strict interdependence between cell subclones. Reducing the amount of growth factors available within a tumor may lead to a reduction in growth followed by a new equilibrium, which may explain relapse in therapies that target growth factors. PMID:25624490

  2. Genetic and Dietary Determinants of Insulin-Like Growth Factor (IGF)-1 and IGF Binding Protein (BP)-3 Levels among Chinese Women

    PubMed Central

    Li, Hui; McCullough, Lauren E.; Qi, Ya-na; Li, Jia-yuan; Zhang, Jing; Miller, Erline; Yang, Chun-xia; Smith, Jennifer S.

    2014-01-01

    Background Higher insulin-like growth factor (IGF)-1 and lower IGF binding protein (BP)-3 levels have been associated with higher commoncancer risk, including breast cancer. Dietary factors, genetic polymorphisms, and the combination of both may influence circulating IGF-1 and IGFBP-3 serum concentrations. Methods From September 2011 to July 2012, we collected demographic, reproductive and dietary data on 143 women (≥40 years). We genotyped IGF-1 rs1520220 and IGFBP-3 rs2854744 and measured circulating IGF-1 and IGFBP-3 levels in serum. Covariance analyses were used to estimate the associations of serum levels of IGF-1 and IGFBP-3, and the molar ratio of IGF-1to IGFBP-3 with IGF-1 rs1520220 and IGFBP-3 rs2854744 genotypes. We subsequently assessed the combined influence of genetics and diet (daily intake of protein, fat and soy isoflavones) on IGF-1 and IGFBP-3 levels. Results Among women aged less than 50 years, circulating IGF-1 serum levels were significantly lower for those with CC genotype for IGF-1 rs1520220 than levels for those with the GC or GG genotypes (in recessive model: P = 0.007).In gene-diet analyses among these women, we found carrying CC genotype for IGF-1 rs1520220 and high soy isoflavone intake tend to be associated with lower circulating IGF-1 levels synthetically (P = 0.002). Women with GG or GC genotypes for IGF-1 rs1520220 and with low intake of soy isoflavones had the highest levels of circulating IGF-1 (geometric mean [95% CI]: 195 [37, 1021] µg/L). Comparatively, women with both the CC genotype and high soy intake had the lowest levels of circulating IGF-1 (geometric mean [95% CI]: 120 [38,378] µg/L). Conclusions IGF-1 serum levels are significantly lower among women with the CC genotype for IGF-1-rs1520220. High soy isoflavone intake may interact with carrying CC genotype for IGF-1-rs1520220 to lower women's serum IGF-1 levels more. PMID:25285521

  3. Development of anxiety-like behavior via hippocampal IGF-2 signaling in the offspring of parental morphine exposure: effect of enriched environment.

    PubMed

    Li, Chang-Qi; Luo, Yan-Wei; Bi, Fang-Fang; Cui, Tao-Tao; Song, Ling; Cao, Wen-Yu; Zhang, Jian-Yi; Li, Fang; Xu, Jun-Mei; Hao, Wei; Xing, Xiao-Wei; Zhou, Fiona H; Zhou, Xin-Fu; Dai, Ru-Ping

    2014-11-01

    Opioid addiction is a major social, economic, and medical problem worldwide. Long-term adverse consequences of chronic opiate exposure not only involve the individuals themselves but also their offspring. Adolescent maternal morphine exposure results in behavior and morphologic changes in the brain of their adult offspring. However, few studies investigate the effect of adult opiate exposure on their offspring. Furthermore, the underlying molecular signals regulating the intergenerational effects of morphine exposure are still elusive. We report here that morphine exposure of adult male and female rats resulted in anxiety-like behavior and dendritic retraction in the dentate gyrus (DG) region of the hippocampus in their adult offspring. The behavior and morphologic changes were concomitant with the downregulation of insulin-like growth factor (IGF)-2 signaling in the granular zone of DG. Overexpression of hippocampal IGF-2 by bilateral intra-DG injection of lentivirus encoding the IGF-2 gene prevented anxiety-like behaviors in the offspring. Furthermore, exposure to an enriched environment during adolescence corrected the reduction of hippocampal IGF-2 expression, normalized anxiety-like behavior and reversed dendritic retraction in the adult offspring. Thus, parental morphine exposure can lead to the downregulation of hippocampal IGF-2, which contributed to the anxiety and hippocampal dendritic retraction in their offspring. An adolescent-enriched environment experience prevented the behavior and morphologic changes in their offspring through hippocampal IGF-2 signaling. IGF-2 and an enriched environment may be a potential intervention to prevention of anxiety and brain atrophy in the offspring of parental opioid exposure. PMID:24889368

  4. Tissue-specific regulation of IGF-I and IGF-binding proteins in response to TNFalpha.

    PubMed

    Lang, C H; Nystrom, G J; Frost, R A

    2001-08-01

    The circulating concentration of insulin-like growth factor-I (IGF-I) is regulated by both its rate of synthesis and its ability to form stable complexes with IGF-binding proteins (IGFBPs). An equilibrium between IGF-I and IGFBPs is thought to help maintain muscle protein balance. In contrast, catabolic conditions disrupt the IGF system and result in the loss of skeletal muscle protein. We have examined the mechanisms by which tumour necrosis factor alpha (TNFalpha), a catabolic cytokine, alters the IGF system. Conscious rats were infused intravenously with recombinant human TNFalpha or vehicle for 24 h. TNFalpha decreased the concentration of both total and free IGF-I in the plasma (30-40%). This change was associated with a reduction in IGF-I mRNA expression in liver (39%), gastrocnemius (73%), soleus (46%) and heart (63%), but a 2.5-fold increase in the whole kidney. In contrast, TNFalpha did not alter IGF-II mRNA expression in skeletal muscle. TNFalpha also increased IGFBP-1 in the blood (4-fold) and this response was associated with an increase in IGFBP-1 mRNA expression in both liver (3-fold) and kidney (9-fold). In contrast, IGFBP-3 levels in the blood were reduced 38% in response to the infusion of TNFalpha. This change was accompanied by a 60-80% reduction of IGFBP-3 mRNA in liver and kidney but no significant change in muscle. Hepatic mRNA levels of the acid-labile subunit were also reduced by TNFalpha (46%). Finally, tissue expression of mac25 (also referred to IGFBP-related protein-1) mRNA was increased in gastrocnemius (50%) but remained unchanged in liver and kidney. These results more fully characterize the changes in various elements of the IGF system and, thereby, provide potential mechanisms for the alterations in the circulating IGF system as well as for changes in tissue metabolism observed during catabolic insults associated with increased TNFalpha expression. PMID:11735242

  5. Seawater and freshwater challenges affect the insulin-like growth factors IGF-I and IGF-II in liver and osmoregulatory organs of the tilapia.

    PubMed

    Link, Karl; Berishvili, Giorgi; Shved, Natallia; D'Cotta, Helena; Baroiller, Jean-François; Reinecke, Manfred; Eppler, Elisabeth

    2010-10-01

    Contradictory studies suggest IGF-I in fish liver and gills is involved in osmoregulation, but nothing is known about the kidney and intestine's role nor about IGF-II's role in any organ. Tilapia were transferred from freshwater (FW) to seawater (SW) for 1week (wk) and retransferred to FW for another week. At 4h, 1d, 2d, 3d and 1wk after SW-transfer and FW-retransfer IGF-I, IGF-II and growth hormone receptor (GHR1) mRNA were measured by real-time PCR. Hepatic IGF-I, IGF-II and GHR1 mRNA were downregulated in parallel after SW-transfer, recovered and were again downregulated after FW-retransfer. In gills, IGF-I, IGF-II and GHR1 were upregulated synchronously after SW-transfer and, partially also after FW-retransfer. The renal genes were downregulated after SW-transfer and partially upregulated after FW-retransfer. Persisting upregulation in intestinal IGF-I mRNA occurred after FW-retransfer. Thus, endocrine and auto/paracrine IGF-I and IGF-II seem to be involved in fish osmoregulation in an organ-specific manner. PMID:20621706

  6. Role of the GH-IGF-1 system in Atlantic salmon and rainbow trout postsmolts at elevated water temperature.

    PubMed

    Hevrøy, Ernst M; Tipsmark, Christian K; Remø, Sofie C; Hansen, Tom; Fukuda, Miki; Torgersen, Thomas; Vikeså, Vibeke; Olsvik, Pål A; Waagbø, Rune; Shimizu, Munetaka

    2015-10-01

    A comparative experiment with Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss) postsmolts was conducted over 35 days to provide insight into how growth, respiration, energy metabolism and the growth hormone (GH) and insulin-like growth factor 1 (IGF-1) system are regulated at elevated sea temperatures. Rainbow trout grew better than Atlantic salmon, and did not show reduced growth at 19 °C. Rainbow trout kept at 19 °C had increased blood hemoglobin concentration compared to rainbow trout kept at 13 °C, while salmon did not show the same hemoglobin response due to increased temperature. Both species showed reduced length growth and decreased muscle glycogen stores at 19 °C. Circulating IGF-1 concentration was higher in rainbow trout than in Atlantic salmon, but was not affected by temperature in either species. Plasma IGF-binding protein 1b (IGFBP-1b) concentration was reduced in Atlantic salmon reared at 19 °C after 15 days but increased in rainbow trout at 19 °C after 35 days. The igfbp1b mRNA level in liver showed a positive correlation to plasma concentrations of glucose and IGFBP-1b, suggesting involvement of this binding protein in carbohydrate metabolism at 19 °C. At this temperature muscle igfbp1a mRNA was down-regulated in both species. The muscle expression of this binding protein correlated negatively with muscle igf1 and length growth. The plasma IGFBP-1b concentration and igfbp1b and igfbp1a expression suggests reduced muscle igf1 signaling at elevated temperature leading to glucose allostasis, and that time course is species specific due to higher thermal tolerance in rainbow trout. PMID:26144599

  7. Effects of recombinant human insulin-like growth factor-I (rhIGF-I) on total and free IGF-I concentrations, IGF-binding proteins, and glycemic response in humans.

    PubMed

    Lieberman, S A; Bukar, J; Chen, S A; Celniker, A C; Compton, P G; Cook, J; Albu, J; Perlman, A J; Hoffman, A R

    1992-07-01

    To examine the effects of repeated administration of recombinant human insulin-like growth factor-I (rhIGF-I) on IGF-I levels, free IGF-I pharmacokinetics, glycemic response, and IGF-binding proteins (IGFBP), we administered rhIGF-I (0.03 mg/kg iv bolus) to 12 healthy males each morning for 5 consecutive days. Serum was collected over 24 h on days 1 and 5 for measurement of total and free IGF-I, glucose, insulin, and IGFBP. Total IGF-I was measured by RIA after acid/ethanol extraction. Free IGF-I was separated from binding protein-complexed IGF-I using size exclusion high performance liquid chromatography before measurement by RIA. IGFBP were quantitated by optical densitometry of Western ligand blots. Total IGF-I increased significantly from 0-24 h after administration on day 1 (mean +/- SD, micrograms/L: 120 +/- 44 to 166 +/- 51, P = 0.0002) but did not increase significantly from 24 h on day 1 to 0 h on day 5 (166 +/- 51 to 178 +/- 62) or from 0-24 h on day 5 (178 +/- 62 to 209 +/- 89). The area under the total IGF-I concentration curve was greater on day 5 than day 1 (311 +/- 99 min.g/L vs. 249 +/- 77, P = 0.0001). There were no significant differences in free IGF-I concentration or pharmacokinetic parameters or in the degree or timing of hypoglycemia between days 1 and 5. Plasma insulin levels decreased significantly following rhIGF-I administration (day 1 baseline: 53 +/- 11 pmol/L, nadir: 18 +/- 6 pmol/L at 30 min, P = 0.003); day 5 baseline: 47 +/- 15 pmol/L, nadir: 16 +/- 8 pmol/L at 30 min, P = 0.0003. Western ligand blotting revealed the transient appearance of a 30-kilodalton band which migrates in a manner similar to IGFBP-1. This band was undetectable at baseline, peaked between 150 and 210 min after rhIGF-I administration, and diminished by 480-600 min. The response was similar on days 1 and 5. There were no substantial changes in the serum levels of any other IGFBP. In summary, repeated iv bolus administration of rhIGF-I increased the level of total

  8. Type 1 IGF receptor translocates to the nucleus of human tumor cells

    PubMed Central

    Aleksic, Tamara; Chitnis, Meenali M.; Perestenko, Olga V.; Gao, Shan; Thomas, Peter H.; Turner, Gareth D.; Protheroe, Andrew S.; Howarth, Mark; Macaulay, Valentine M.

    2010-01-01

    The type 1 insulin-like growth factor receptor (IGF-1R) is a transmembrane glycoprotein comprising two extracellular α subunits and two β subunits with tyrosine kinase activity. The IGF-1R is frequently upregulated in cancers, and signals from the cell surface to promote proliferation and cell survival. Recent attention has focused on the IGF-1R as a target for cancer treatment. Here we report that the nuclei of human tumor cells contain IGF-1R, detectable using multiple antibodies to α- and β- subunit domains. Cell surface IGF-1R translocates to the nucleus following clathrin-mediated endocytosis, regulated by IGF levels. The IGF-1R is unusual among transmembrane receptors that undergo nuclear import, in that both α and β subunits traffic to the nucleus. Nuclear IGF-1R is phosphorylated in response to ligand, and undergoes IGF-induced interaction with chromatin, suggesting direct engagement in transcriptional regulation. The IGF-dependence of these phenomena indicate a requirement for the receptor kinase, and indeed IGF-1R nuclear import and chromatin binding can be blocked by a novel IGF-1R kinase inhibitor. Nuclear IGF-1R is detectable in primary renal cancer cells, formalin-fixed tumors, preinvasive lesions in the breast, and non-malignant tissues characterized by a high proliferation rate. In clear cell renal cancer, nuclear IGF-1R is associated with adverse prognosis. Our findings suggest that IGF-1R nuclear import has biological significance, may contribute directly to IGF-1R function, and may influence the efficacy of IGF-1R inhibitory drugs. PMID:20710042

  9. The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

    PubMed Central

    Philippou, Anastassios; Maridaki, Maria; Pneumaticos, Spiros; Koutsilieris, Michael

    2014-01-01

    The insulinlike growth factor-I (IGF-I) is an important factor which regulates a variety of cellular responses in multiple biological systems. The IGF1 gene comprises a highly conserved sequence and contains six exons, which give rise to heterogeneous mRNA transcripts by a combination of multiple transcription initiation sites and alternative splicing. These multiple transcripts code for different precursor IGF-I polypeptides, namely the IGF-IEa, IGF-IEb and IGF-IEc isoforms in humans, which also undergo posttranslational modifications, such as proteolytic processing and glycosylation. IGF-I actions are mediated through its binding to several cell-membrane receptors and the IGF-I domain responsible for the receptor binding is the bioactive mature IGF-I peptide, which is derived after the posttranslational cleavage of the pro-IGF-I isoforms and the removal of their carboxy-terminal E-peptides (that is, the Ea, Eb and Ec). Interestingly, differential biological activities have been reported for the different IGF-I isoforms, or for their E-peptides, implying that IGF-I peptides other than the IGF-I ligand also possess bioactivity and, thus, both common and unique or complementary pathways exist for the IGF-I isoforms to promote biological effects. The multiple peptides derived from IGF-I and the differential expression of its various transcripts in different conditions and pathologies appear to be compatible with the distinct cellular responses observed to the different IGF-I peptides and with the concept of a complex and possibly isoform-specific IGF-I bioactivity. This concept is discussed in the present review, in the context of the broad range of modifications that this growth factor undergoes which might regulate its mechanism(s) of action. PMID:24637928

  10. Native and Complexed IGF-1: Biodistribution and Pharmacokinetics in Infantile Neuronal Ceroid Lipofuscinosis

    PubMed Central

    Huhtala, Tuulia; Rytkönen, Jussi; Jalanko, Anu; Kaasalainen, Martti; Salonen, Jarno; Riikonen, Raili; Närvänen, Ale

    2012-01-01

    Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerative disorder of childhood characterized by selective death of cortical neurons. Insulin-like growth factor 1 (IGF-1) is important in embryonic development and is considered as a potential therapeutic agent for several disorders of peripheral and central nervous systems. In circulation IGF-1 is mainly bound to its carrier protein IGFBP-3. As a therapeutic agent IGF-1 has shown to be more active as free than complexed form. However, this may cause side effects during the prolonged treatment. In addition to IGFBP-3 the bioavailability of IGF-1 can be modulated by using mesoporous silicon nanoparticles (NPs) which are optimal carriers for sustained release of unstable peptide hormones like IGF-1. In this study we compared biodistribution, pharmacokinetics, and bioavailability of radiolabeled free IGF-1, IGF-1/IGFBP-3, and IGF-1/NP complexes in a Cln1-/- knockout mouse model. IGF-1/NP was mainly accumulated in liver and spleen in all studied time points, whereas minor and more constant amounts were measured in other organs compared to free IGF-1 or IGF-1/IGFBP-3. Also concentration of IGF-1/NP in blood was relatively high and stable during studied time points suggesting continuous release of IGF-1 from the particles. PMID:22778966

  11. Abnormal IGF-Binding Protein Profile in the Bone Marrow of Multiple Myeloma Patients

    PubMed Central

    Bieghs, Liesbeth; Brohus, Malene; Kristensen, Ida B.; Abildgaard, Niels; Bøgsted, Martin; Johnsen, Hans E.; Conover, Cheryl A.; De Bruyne, Elke; Vanderkerken, Karin

    2016-01-01

    Insulin-like growth factor (IGF) signalling plays a key role in homing, progression, and treatment resistance in multiple myeloma (MM). In the extracellular environment, the majority of IGF molecules are bound to one of six IGF-binding proteins (IGFBP1-6), leaving a minor fraction of total IGF free and accessible for receptor activation. In MM, high IGF-receptor type 1 expression levels correlate with a poor prognosis, but the status and role of IGF and IGFBPs in the pathobiology of MM is unknown. Here we measured total IGF1, IGF2, and intact IGFBP levels in blood and bone marrow samples from MM (n = 17), monoclonal gammopathy of undetermined significance (MGUS) (n = 37), and control individuals (n = 15), using ELISA (IGFs) and 125I-IGF1 Western Ligand Blotting (IGFBPs). MGUS and MM patients displayed a significant increase in intact IGFBP-2 (2.5–3.8 fold) and decrease in intact IGFBP-3 (0.6–0.5 fold) in the circulation compared to control individuals. Further, IGFBP-2 as well as total IGFBP levels were significantly lower in bone marrow compared to circulation in MM and MGUS only, whereas IGF1, IGF2, and IGFBP-3 were equally distributed between the two compartments. In conclusion, the profound change in IGFBP profile strongly suggests an increased IGF bioavailability in the bone marrow microenvironment in MGUS and MM, despite no change in growth factor concentration. PMID:27111220

  12. Abnormal IGF-Binding Protein Profile in the Bone Marrow of Multiple Myeloma Patients.

    PubMed

    Bieghs, Liesbeth; Brohus, Malene; Kristensen, Ida B; Abildgaard, Niels; Bøgsted, Martin; Johnsen, Hans E; Conover, Cheryl A; De Bruyne, Elke; Vanderkerken, Karin; Overgaard, Michael T; Nyegaard, Mette

    2016-01-01

    Insulin-like growth factor (IGF) signalling plays a key role in homing, progression, and treatment resistance in multiple myeloma (MM). In the extracellular environment, the majority of IGF molecules are bound to one of six IGF-binding proteins (IGFBP1-6), leaving a minor fraction of total IGF free and accessible for receptor activation. In MM, high IGF-receptor type 1 expression levels correlate with a poor prognosis, but the status and role of IGF and IGFBPs in the pathobiology of MM is unknown. Here we measured total IGF1, IGF2, and intact IGFBP levels in blood and bone marrow samples from MM (n = 17), monoclonal gammopathy of undetermined significance (MGUS) (n = 37), and control individuals (n = 15), using ELISA (IGFs) and 125I-IGF1 Western Ligand Blotting (IGFBPs). MGUS and MM patients displayed a significant increase in intact IGFBP-2 (2.5-3.8 fold) and decrease in intact IGFBP-3 (0.6-0.5 fold) in the circulation compared to control individuals. Further, IGFBP-2 as well as total IGFBP levels were significantly lower in bone marrow compared to circulation in MM and MGUS only, whereas IGF1, IGF2, and IGFBP-3 were equally distributed between the two compartments. In conclusion, the profound change in IGFBP profile strongly suggests an increased IGF bioavailability in the bone marrow microenvironment in MGUS and MM, despite no change in growth factor concentration. PMID:27111220

  13. Native and Complexed IGF-1: Biodistribution and Pharmacokinetics in Infantile Neuronal Ceroid Lipofuscinosis.

    PubMed

    Huhtala, Tuulia; Rytkönen, Jussi; Jalanko, Anu; Kaasalainen, Martti; Salonen, Jarno; Riikonen, Raili; Närvänen, Ale

    2012-01-01

    Infantile neuronal ceroid lipofuscinosis (INCL) is a severe neurodegenerative disorder of childhood characterized by selective death of cortical neurons. Insulin-like growth factor 1 (IGF-1) is important in embryonic development and is considered as a potential therapeutic agent for several disorders of peripheral and central nervous systems. In circulation IGF-1 is mainly bound to its carrier protein IGFBP-3. As a therapeutic agent IGF-1 has shown to be more active as free than complexed form. However, this may cause side effects during the prolonged treatment. In addition to IGFBP-3 the bioavailability of IGF-1 can be modulated by using mesoporous silicon nanoparticles (NPs) which are optimal carriers for sustained release of unstable peptide hormones like IGF-1. In this study we compared biodistribution, pharmacokinetics, and bioavailability of radiolabeled free IGF-1, IGF-1/IGFBP-3, and IGF-1/NP complexes in a Cln1-/- knockout mouse model. IGF-1/NP was mainly accumulated in liver and spleen in all studied time points, whereas minor and more constant amounts were measured in other organs compared to free IGF-1 or IGF-1/IGFBP-3. Also concentration of IGF-1/NP in blood was relatively high and stable during studied time points suggesting continuous release of IGF-1 from the particles. PMID:22778966

  14. Cellular localization and expression of insulin-like growth factors (IGFs) and IGF binding proteins within the epiphyseal growth plate of the ovine fetus: possible functional implications.

    PubMed

    de los Rios, P; Hill, D J

    1999-04-01

    The insulin-like growth factors (IGFs) are important in the regulation of normal fetal musculoskeletal growth and development, and their actions have been shown to be modulated by IGF binding proteins (IGFBPs). Because the anatomical distribution of IGFBPs is likely to dictate IGF bioavailability, we determined the cellular distribution and expression of IGF-I, IGF-II, and IGFBP-1 to IGFBP-6 in epiphyseal growth plates of the fetal sheep, using immunocytochemistry and in situ hybridization. Little mRNA for IGF-I was detectable within the growth plates, but mRNA for IGF-II was abundant in germinal and proliferative chondrocytes, although absent from some differentiating chondrocytes and hypertrophic cells. Immunohistochemistry for IGF-I and IGF-II showed a presence of both peptides in all chondrocyte zones, including hypertrophic cells. Immunoreactive IGFBP-2 to -5 were localized within the germinal and proliferative zones of chondrocytes, but little immunoreactivity was present within the columns of differentiating cells. IGFBP immunoreactivity again appeared in hypertrophic chondrocytes. IGFBP mRNA in chondrocytes of the epiphyseal growth plate was below the detectable limit of in situ hybridization. However, low levels of mRNAs for IGFBP-2 to -6 were detected by the reverse transcriptase polymerase chain reaction. A co-localization of IGFBPs with IGF peptides in intact cartilage suggests that they may regulate IGF bioavailability and action locally. To test this hypothesis, monolayer cultures of chondrocytes were established from the proliferative zone of the growth plate, and were found to release immunoreactive IGF-II and to express mRNAs encoding IGFBP-2 to -6. Exogenous IGFBP-3, -4, and -5 had an inhibitory action on IGF-II-dependent DNA synthesis. IGFBP-2 had a biphasic effect, potentiating IGF-II action at low concentrations but inhibiting DNA synthesis at equimolar or greater concentrations relative to IGF-II. Long R3 IGF-I, which has a reduced binding

  15. The GH/IGF-1 axis in ageing and longevity

    PubMed Central

    List, Edward O.; Berryman, Darlene E.; Murrey, John W.

    2014-01-01

    Secretion of growth hormone (GH), and consequently that of insulin-like growth factor 1 (IGF-1), declines over time until only low levels can be detected in individuals aged ≥60 years. This phenomenon, which is known as the ‘somatopause’, has led to recombinant human GH being widely promoted and abused as an antiageing drug, despite lack of evidence of efficacy. By contrast, several mutations that decrease the tone of the GH/IGF-1 axis are associated with extended longevity in mice. In humans, corresponding or similar mutations have been identified, but whether these mutations alter longevity has yet to be established. The powerful effect of reduced GH activity on lifespan extension in mice has generated the hypothesis that pharmaceutically inhibiting, rather than increasing, GH action might delay ageing. Moreover, mice as well as humans with reduced activity of the GH/IGF-1 axis are protected from cancer and diabetes mellitus, two major ageing-related morbidities. Here, we review data on mouse strains with alterations in the GH/IGF-1 axis and their effects on lifespan. The outcome of corresponding or similar mutations in humans is described, as well as the potential mechanisms underlying increased longevity and the therapeutic benefits and risks of medical disruption of the GH/IGF-1 axis in humans. PMID:23591370

  16. Intranasal IGF-1 Reduced Rat Pup Germinal Matrix Hemorrhage.

    PubMed

    Lekic, Tim; Flores, Jerry; Klebe, Damon; Doycheva, Desislava; Rolland, William B; Tang, Jiping; Zhang, John H

    2016-01-01

    Germinal matrix hemorrhage (GMH) is the most devastating neurological problem of premature infants. Current treatment strategies are ineffective and brain injury is unpreventable. Insulin-like growth factor 1 (IGF-1) is an endogenous protein shown to have multiple neuroprotective properties. We therefore hypothesized that IGF-1 would reduce brain injury after GMH. Neonatal rats (P7 age) received stereotactic collagenase into the right ganglionic eminence. The following groups were studied: (1) sham, (2) GMH + vehicle, (3) GMH + intranasal IGF-1. Three days later, the animals were evaluated using the righting-reflex (early neurobehavior), Evans blue dye leakage (blood-brain barrier (BBB) permeability), brain water content (edema), and hemoglobin assay (extent of bleeding). Three weeks later, juvenile rats were tested using a water maze (delayed neurobehavior), and then were sacrificed on day 28 for assessment of hydrocephalus (ventricular size). Intranasal IGF-1 treated animals had improved neurological function, and amelioration of BBB permeability, edema, and re-bleeding. IGF-1 may play a part in protective brain signaling following GMH, and our observed protective effect may offer new promise for treatment targeting this vulnerable patient population. PMID:26463950

  17. Role and Importance of IGF-1 in Traumatic Brain Injuries

    PubMed Central

    Mangiola, Annunziato; Vigo, Vera; Anile, Carmelo; De Bonis, Pasquale; Marziali, Giammaria; Lofrese, Giorgio

    2015-01-01

    It is increasingly affirmed that most of the long-term consequences of TBI are due to molecular and cellular changes occurring during the acute phase of the injury and which may, afterwards, persist or progress. Understanding how to prevent secondary damage and improve outcome in trauma patients, has been always a target of scientific interest. Plans of studies focused their attention on the posttraumatic neuroendocrine dysfunction in order to achieve a correlation between hormone blood level and TBI outcomes. The somatotropic axis (GH and IGF-1) seems to be the most affected, with different alterations between the acute and late phases. IGF-1 plays an important role in brain growth and development, and it is related to repair responses to damage for both the central and peripheral nervous system. The IGF-1 blood levels result prone to decrease during both the early and late phases after TBI. Despite this, experimental studies on animals have shown that the CNS responds to the injury upregulating the expression of IGF-1; thus it appears to be related to the secondary mechanisms of response to posttraumatic damage. We review the mechanisms involving IGF-1 in TBI, analyzing how its expression and metabolism may affect prognosis and outcome in head trauma patients. PMID:26417600

  18. Crosstalk between Insulin/IGF-1 and GPCR Signaling Systems: A Novel Target for the Anti-diabetic Drug Metformin in Pancreatic Cancer#

    PubMed Central

    Rozengurt, Enrique; Sinnett-Smith, James; Kisfalvi, Krisztina

    2010-01-01

    Insulin/insulin-like growth factor 1(IGF-1) receptors and G protein-coupled receptors (GPCR) signaling systems are implicated in autocrine/paracrine stimulation of a variety of malignancies, including ductal adenocarcinoma of the pancreas, one of the most lethal human diseases. Novel targets for pancreatic cancer therapy are urgently needed. We identified a crosstalk between insulin/IGF-1 receptors and GPCR signaling systems in pancreatic cancer cells, leading to enhanced signaling, DNA synthesis and proliferation. Crosstalk between these signaling systems depends on mTOR complex 1 (mTORC1). Metformin, the most widely used drug in the treatment of type-2 diabetes, activates AMP kinase (AMPK), which negatively regulates mTORC1. Recent results show that metformin-induced activation of AMPK disrupts crosstalk between insulin/IGF-1 receptor and GPCR signaling in pancreatic cancer cells and inhibits the growth of these cells in xenograft models. Given that insulin/IGF-1 and GPCRs are implicated in other malignancies, a similar crosstalk mechanism may be operative in other cancer cell types. Recent epidemiological studies linked administration of metformin with a reduced risk of pancreatic, breast and prostate cancer in diabetic patients. We posit that crosstalk between insulin/IGF-1 receptor and GPCR signaling is a mechanism for promoting the development of certain types of cancer and a target for the prevention and therapy of these diseases via metformin administration. PMID:20388847

  19. Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndrome.

    PubMed

    Melnik, Bodo C; John, Swen Malte; Schmitz, Gerd

    2011-01-01

    The insulin/insulin-like growth factor-1 (IGF-1) pathway drives an evolutionarily conserved network that regulates lifespan and longevity. Individuals with Laron syndrome who carry mutations in the growth hormone receptor (GHR) gene that lead to severe congenital IGF-1 deficiency with decreased insulin/IGF-1 signaling (IIS) exhibit reduced prevalence rates of acne, diabetes and cancer. Western diet with high intake of hyperglycemic carbohydrates and insulinotropic dairy over-stimulates IIS. The reduction of IIS in Laron subjects unmasks the potential role of persistent hyperactive IIS mediated by Western diet in the development of diseases of civilization and offers a rational perspective for dietary adjustments with less insulinotropic diets like the Paleolithic diet. PMID:21699736

  20. Optimisation of a 5-[3-phenyl-(2-cyclic-ether)-methyl-ether]-4-aminopyrrolopyrimidine series of IGF-1R inhibitors.

    PubMed

    Fairhurst, Robin A; Marsilje, Thomas H; Stutz, Stefan; Boos, Andreas; Niklaus, Michel; Chen, Bei; Jiang, Songchun; Lu, Wenshuo; Furet, Pascal; McCarthy, Clive; Stauffer, Frédéric; Guagnano, Vito; Vaupel, Andrea; Michellys, Pierre-Yves; Schnell, Christian; Jeay, Sébastien

    2016-04-15

    Taking the pyrrolopyrimidine derived IGF-1R inhibitor NVP-AEW541 as the starting point, the benzyl ether back-pocket binding moiety was replaced with a series of 2-cyclic ether methyl ethers leading to the identification of novel achiral [2.2.1]-bicyclic ether methyl ether containing analogues with improved IGF-1R activities and kinase selectivities. Further exploration of the series, including a fluorine scan of the 5-phenyl substituent, and optimisation of the sugar-pocket binding moiety identified compound 33 containing (S)-2-tetrahydrofuran methyl ether 6-fluorophenyl ether back-pocket, and cis-N-Ac-Pip sugar-pocket binding groups. Compound 33 showed improved selectivity and pharmacokinetics compared to NVP-AEW541, and produced comparable in vivo efficacy to linsitinib in inhibiting the growth of an IGF-1R dependent tumour xenograft model in the mouse. PMID:26951753

  1. Chondrocyte IGF-1 receptor expression and responsiveness to IGF-1 stimulation in mouse articular cartilage during various phases of experimentally induced arthritis.

    PubMed Central

    Verschure, P J; van Marle, J; Joosten, L A; van den Berg, W B

    1995-01-01

    OBJECTIVE--To examine the distribution of insulin like growth factor-1 (IGF-1) receptors and the biological response to IGF-1 stimulation in articular cartilage of normal mouse knee joints and arthritic joints taken at various stages of experimentally induced arthritis. METHODS--In situ IGF-1 receptor expression and responsiveness to IGF-1 stimulation were examined in murine articular cartilage at different phases in two models of experimentally induced arthritis. IGF-1 receptor expression was visualised in joint sections with the use of anti-IGF-1 receptor antibodies and quantified by confocal laser scanning microscopy. Chondrocyte proteoglycan (PG) synthesis was measured by incorporation of 35S-sulphate. RESULTS--In control cartilage, the majority of IGF-1 receptors were found on chondrocytes localised in the middle and deeper zones of the cartilage, whereas receptor expression in surface zone chondrocytes was very low. During culture of normal articular cartilage, IGF-1 was able to maintain chondrocyte PG synthesis at the in vivo level. Concurrently with the development of arthritis, cartilage lost its capacity to react to IGF-1, but IGF-1 stimulation recovered when the inflammatory response waned. Shortly after induction of arthritis, IGF-1 receptor expression initially declined, but it had returned to normal levels by day 1 and remained increased thereafter. CONCLUSION--The distribution of IGF-1 receptor expression in the different zones of normal articular cartilage reflects IGF-1 stimulation and metabolic activity of chondrocytes in these layers. This correlation is disturbed in arthritic cartilage, suggesting inadequate or overruled signalling. Images PMID:7677441

  2. ERG deregulation induces IGF-1R expression in prostate cancer cells and affects sensitivity to anti-IGF-1R agents.

    PubMed

    Mancarella, Caterina; Casanova-Salas, Irene; Calatrava, Ana; Ventura, Selena; Garofalo, Cecilia; Rubio-Briones, José; Magistroni, Vera; Manara, Maria Cristina; López-Guerrero, José Antonio; Scotlandi, Katia

    2015-06-30

    Identifying patients who may benefit from targeted therapy is an urgent clinical issue in prostate cancer (PCa). We investigated the molecular relationship between TMPRSS2-ERG (T2E) fusion gene and insulin-like growth factor receptor (IGF-1R) to optimize the use of IGF-1R inhibitors.IGF-1R was analyzed in cell lines and in radical prostatectomy specimens in relation to T2E status. ERG binding to IGF-1R promoter was evaluated by chromatin immunoprecipitation (ChIP). Sensitivity to anti-IGF-1R agents was evaluated alone or in combination with anti-androgen abiraterone acetate in vitro at basal levels or upon ERG modulation.IGF-1R analysis performed in PCa cells or clinical samples showed that T2E expression correlated with higher IGF-1R expression at mRNA and protein levels. Genetic modulation of ERG directly affected IGF-1R protein levels in vitro. ChIP analysis showed that ERG binds IGF-1R promoter and that promoter occupancy is higher in T2E-positive cells. IGF-1R inhibition was more effective in cell lines expressing the fusion gene and combination of IGF-1R inhibitors with abiraterone acetate produced synergistic effects in T2E-expressing cells.Here, we provide the rationale for use of T2E fusion gene to select PCa patients for anti-IGF-1R treatments. The combination of anti-IGF-1R-HAbs with an anti-androgen therapy is strongly advocated for patients expressing T2E. PMID:25906745

  3. Impact of PTEN on the expression of insulin-like growth factors (IGFs) and IGF-binding proteins in human gastric adenocarcinoma cells

    SciTech Connect

    Yi, Ho-Keun; Kim, Sun-Young; Hwang, Pyoung-Han; Kim, Chan-Young; Yang, Doo-Hyun; Oh, Youngman; Lee, Dae-Yeol . E-mail: leedy@chonbuk.ac.kr

    2005-05-13

    PTEN is a tumor suppressor gene that is frequently mutated or deleted in a variety of human cancers including human gastric cancer. PTEN functions primarily as a lipid phosphatase and plays a key role in the regulation of the PI3 kinase/Akt pathway, thereby modulating cell proliferation and cell survival. On the other hand, the IGF system plays an important role in cell proliferation and cell survival via the PI3 kinase/Akt and MAP kinase pathways in many cancer cells. To characterize the impact of PTEN on the IGF-IGFR-IGFBP axis in gastric cancer, we overexpressed PTEN using an adenovirus gene transfer system in human gastric adenocarcinoma cells, SNU-484 and SNU-663, which lack PTEN. Overexpression of PTEN inhibited serum-induced as well as IGF-I-induced cell proliferation as compared to control cells. PTEN overexpression resulted in a significant decrease in the expression of IGF-I, -II, and IGF-IR. Interestingly, amongst the six IGFBPs, only IGFBP-3 was upregulated by PTEN, whereas IGFBP-4 and -6 were reduced. The IGFBP-3 promoter activity assay and Western immunoblotting demonstrate that PTEN regulates IGFBP-3 at the transcriptional level. In addition, the PI3 kinase inhibitor, LY294002, upregulates IGFBP-3 expression but downregulates IGF-I and IGF-II, indicating that PTEN controls IGFBP-3 and IGFs by an Akt-dependent pathway. These findings suggest that PTEN may inhibit antiapoptotic IGF actions not only by blocking the IGF-IGFR-induced Akt activity, but also by regulating expression of components of the IGF system, in particular, upregulation of IGFBP-3, which is known to exert antiproliferative effects through IGF-dependent and IGF-independent mechanisms in cancer cells.

  4. ERG deregulation induces IGF-1R expression in prostate cancer cells and affects sensitivity to anti-IGF-1R agents

    PubMed Central

    Mancarella, Caterina; Casanova-Salas, Irene; Calatrava, Ana; Ventura, Selena; Garofalo, Cecilia; Rubio-Briones, José; Magistroni, Vera; Manara, Maria Cristina; López-Guerrero, José Antonio; Scotlandi, Katia

    2015-01-01

    Identifying patients who may benefit from targeted therapy is an urgent clinical issue in prostate cancer (PCa). We investigated the molecular relationship between TMPRSS2-ERG (T2E) fusion gene and insulin-like growth factor receptor (IGF-1R) to optimize the use of IGF-1R inhibitors. IGF-1R was analyzed in cell lines and in radical prostatectomy specimens in relation to T2E status. ERG binding to IGF-1R promoter was evaluated by chromatin immunoprecipitation (ChIP). Sensitivity to anti-IGF-1R agents was evaluated alone or in combination with anti-androgen abiraterone acetate in vitro at basal levels or upon ERG modulation. IGF-1R analysis performed in PCa cells or clinical samples showed that T2E expression correlated with higher IGF-1R expression at mRNA and protein levels. Genetic modulation of ERG directly affected IGF-1R protein levels in vitro. ChIP analysis showed that ERG binds IGF-1R promoter and that promoter occupancy is higher in T2E-positive cells. IGF-1R inhibition was more effective in cell lines expressing the fusion gene and combination of IGF-1R inhibitors with abiraterone acetate produced synergistic effects in T2E-expressing cells. Here, we provide the rationale for use of T2E fusion gene to select PCa patients for anti-IGF-1R treatments. The combination of anti-IGF-1R-HAbs with an anti-androgen therapy is strongly advocated for patients expressing T2E. PMID:25906745

  5. Deletion of muscle GRP94 impairs both muscle and body growth by inhibiting local IGF production

    PubMed Central

    Barton, Elisabeth R.; Park, SooHyun; James, Jose K.; Makarewich, Catherine A.; Philippou, Anastassios; Eletto, Davide; Lei, Hanqin; Brisson, Becky; Ostrovsky, Olga; Li, Zihai; Argon, Yair

    2012-01-01

    Insulin-like growth factors (IGFs) are critical for development and growth of skeletal muscles, but because several tissues produce IGFs, it is not clear which source is necessary or sufficient for muscle growth. Because it is critical for production of both IGF-I and IGF-II, we ablated glucose-regulated protein 94 (GRP94) in murine striated muscle to test the necessity of local IGFs for normal muscle growth. These mice exhibited smaller skeletal muscles with diminished IGF contents but with normal contractile function and no apparent endoplasmic reticulum stress response. This result shows that muscles rely on GRP94 primarily to support local production of IGFs, a pool that is necessary for normal muscle growth. In addition, body weights were ∼30% smaller than those of littermate controls, and circulating IGF-I also decreased significantly, yet glucose homeostasis was maintained with little disruption to the growth hormone pathway. The growth defect was complemented on administration of recombinant IGF-I. Thus, unlike liver production of IGF-I, muscle IGF-I is necessary not only locally but also globally for whole-body growth.—Barton, E. R., Park, S., James, J. K., Makarewich, C. A., Philippou, A., Eletto, D., Lei, H., Brisson, B., Ostrovsky, O., Li, Z., Argon, Y. Deletion of muscle GRP94 impairs both muscle and body growth by inhibiting local IGF production. PMID:22649033

  6. Role of IGF-I in follistatin-induced skeletal muscle hypertrophy.

    PubMed

    Barbé, Caroline; Kalista, Stéphanie; Loumaye, Audrey; Ritvos, Olli; Lause, Pascale; Ferracin, Benjamin; Thissen, Jean-Paul

    2015-09-15

    Follistatin, a physiological inhibitor of myostatin, induces a dramatic increase in skeletal muscle mass, requiring the type 1 IGF-I receptor/Akt/mTOR pathway. The aim of the present study was to investigate the role of IGF-I and insulin, two ligands of the IGF-I receptor, in the follistatin hypertrophic action on skeletal muscle. In a first step, we showed that follistatin increases muscle mass while being associated with a downregulation of muscle IGF-I expression. In addition, follistatin retained its full hypertrophic effect toward muscle in hypophysectomized animals despite very low concentrations of circulating and muscle IGF-I. Furthermore, follistatin did not increase muscle sensitivity to IGF-I in stimulating phosphorylation of Akt but, surprisingly, decreased it once hypertrophy was present. Taken together, these observations indicate that increased muscle IGF-I production or sensitivity does not contribute to the muscle hypertrophy caused by follistatin. Unlike low IGF-I, low insulin, as obtained by streptozotocin injection, attenuated the hypertrophic action of follistatin on skeletal muscle. Moreover, the full anabolic response to follistatin was restored in this condition by insulin but also by IGF-I infusion. Therefore, follistatin-induced muscle hypertrophy requires the activation of the insulin/IGF-I pathway by either insulin or IGF-I. When insulin or IGF-I alone is missing, follistatin retains its full anabolic effect, but when both are deficient, as in streptozotocin-treated animals, follistatin fails to stimulate muscle growth. PMID:26219865

  7. A Human Variant of Glucose-Regulated Protein 94 That Inefficiently Supports IGF Production.

    PubMed

    Marzec, Michal; Hawkes, Colin P; Eletto, Davide; Boyle, Sarah; Rosenfeld, Ron; Hwa, Vivian; Wit, Jan M; van Duyvenvoorde, Hermine A; Oostdijk, Wilma; Losekoot, Monique; Pedersen, Oluf; Yeap, Bu Beng; Flicker, Leon; Barzilai, Nir; Atzmon, Gil; Grimberg, Adda; Argon, Yair

    2016-05-01

    IGFs are critical for normal intrauterine and childhood growth and sustaining health throughout life. We showed previously that the production of IGF-1 and IGF-2 requires interaction with the chaperone glucose-regulated protein 94 (GRP94) and that the amount of secreted IGFs is proportional to the GRP94 activity. Therefore, we tested the hypothesis that functional polymorphisms of human GRP94 affect IGF production and thereby human health. We describe a hypomorphic variant of human GRP94, P300L, whose heterozygous carriers have 9% lower circulating IGF-1 concentration. P300L was found first in a child with primary IGF deficiency and was later shown to be a noncommon single-nucleotide polymorphism with frequencies of 1%-4% in various populations. When tested in the grp94(-/-) cell-based complementation assay, P300L supported only approximately 58% of IGF secretion relative to wild-type GRP94. Furthermore, recombinant P300L showed impaired nucleotide binding activity. These in vitro data strongly support a causal relationship between the GRP94 variant and the decreased concentration of circulating IGF-1, as observed in human carriers of P300L. Thus, mutations in GRP94 that affect its IGF chaperone activity represent a novel causal genetic mechanism that limits IGF biosynthesis, quite a distinct mechanism from the known genes in the GH/IGF signaling network. PMID:26982636

  8. IGF-I Stimulates Rab7-RILP Interaction During Neuronal Autophagy

    PubMed Central

    Bains, Mona; Zaegel, Vincent; Mize-Berge, Janna; Heidenreich, Kim A.

    2011-01-01

    Restoration of autophagy represents a potential therapeutic target for neurodegenerative disorders, but factors that regulate autophagic flux are largely unknown. When deprived of trophic factors, cultured Purkinje neurons die by an autophagy associated cell death mechanism. The accumulation of autophagic vesicles and cell death of Purkinje neurons is inhibited by insulin-like growth factor, by a mechanism that enhances autophagic vesicle turnover. In this report, we identify Rab7 as an IGF-I regulated target during neuronal autophagy. Purkinje neurons transfected with EGFP-Rab7-WT and constitutively active EGFP-Rab7-Q67L contained few RFP-LC3 positive autophagosomes and little co-localization with GFP-Rab7 under control conditions. Upon induction of autophagy, RFP-LC3 positive autophagosomes increased and co-localized with GFP-Rab7. Conversely, expression of the dominant negative mutant EGFP-Rab7-T22N increased the accumulation of autophagosomes under control conditions, which accumulated even further during trophic factor withdrawal. There was no vesicular co-localization between Rab7-T22N and RFP-LC3 under control or trophic factor withdrawal conditions. During prolonged trophic factor withdrawal, a condition that leads to the accumulation of autophagic vesicles and cell death, Rab7 activity decreased significantly. IGF-I, added at the time of trophic factor withdrawal, prevented the deactivation of Rab7 and increased the interaction of Rab7 with its interacting protein (RILP), restoring autophagic flux. These results provide a novel mechanism by which IGF-I regulates autophagic flux during neuronal stress. PMID:20849920

  9. Angelica Sinensis Polysaccharides Stimulated UDP-Sugar Synthase Genes through Promoting Gene Expression of IGF-1 and IGF1R in Chondrocytes: Promoting Anti-Osteoarthritic Activity

    PubMed Central

    Wen, Yinxian; Li, Jing; Tan, Yang; Qin, Jun; Xie, Xianfei; Wang, Linlong; Mei, Qibing; Wang, Hui; Magdalou, Jacques; Chen, Liaobin

    2014-01-01

    Background Osteoarthritis (OA) is a chronic joints disease characterized by progressive degeneration of articular cartilage due to the loss of cartilage matrix. Previously, we found, for the first time, that an acidic glycan from Angelica Sinensis Polysaccharides (APSs), namely the APS-3c, could protect rat cartilage from OA due to promoting glycosaminoglycan (GAG) synthesis in chondrocytes. In the present work, we tried to further the understanding of ASP-3c’s anti-OA activity. Methodology/Principal Findings Human primary chondrocytes were treated with APS-3c or/and recombinant human interleukin 1β (IL-1β). It turned out that APS-3c promoted synthesis of UDP-xylose and GAG, as well as the gene expression of UDP-sugar synthases (USSs), insulin like growth factor 1 (IGF1) and IGF1 receptor (IGF1R), and attenuated the degenerative phenotypes, suppressed biosynthesis of UDP-sugars and GAG, and inhibited the gene expression of USSs, IGF1 and IGF1R induced by IL-1β. Then, we induced a rat OA model with papain, and found that APS-3c also stimulated GAG synthesis and gene expression of USSs, IGF1 and IGF1R in vivo. Additionally, recombinant human IGF1 and IGF1R inhibitor NP-AEW541 were applied to figure out the correlation between stimulated gene expression of USSs, IGF1 and IGF1R induced by APS-3c. It tuned out that the promoted GAG synthesis and USSs gene expression induced by APS-3c was mediated by the stimulated IGF1 and IGF1R gene expression, but not through directly activation of IGF1R signaling pathway. Conclusions/Significances We demonstrated for the first time that APS-3c presented anti-OA activity through stimulating IGF-1 and IGF1R gene expression, but not directly activating the IGF1R signaling pathway, which consequently promoted UDP-sugars and GAG synthesis due to up-regulating gene expression of USSs. Our findings presented a better understanding of APS-3c’s anti-OA activity and suggested that APS-3c could potentially be a novel therapeutic agent

  10. Radioimmunoassay for insulin-like growth factor II (IGF-II).

    PubMed

    Asakawa, K; Hizuka, N; Takano, K; Fukuda, I; Sukegawa, I; Demura, H; Shizume, K

    1990-10-01

    Insulin-like growth factor II (IGF-II) levels in human plasma were measured in physiological and pathological conditions by radioimmunoassay (RIA) with biosynthetic IGF-II. This RIA was specific for IGF-II and cross-reactivity with IGF-I was 1%. The sensitivity was 15 pg/tube with 50% displacement at 50 pg/tube. The intra- and inter-assay coefficients of variation for IGF-II were 6.3 and 9.3%, respectively. The plasma IGF-II levels in normal adults, patients with hypopituitarism and patients with active acromegaly were 589.6 +/- 15.8, 800.9 +/- 45.6 and 330.3 +/- 24.3 ng/ml, respectively. After human growth hormone (hGH) treatment in hypopituitarism, IGF-II slightly increased, but not significantly. After adenomectomy in patients with acromegaly, IGF-II significantly decreased. These data indicate that IGF-II concentrations in plasma were partially GH dependent. This GH dependency was less than that of IGF-I. IGF-II was low in patients with anorexia nervosa and with liver cirrhosis and high in patients with renal failure. In two cases with extrapancreatic tumor-associated hypoglycemia, plasma IGF-II was increased to 1123.8 and 843.5 ng/ml, and returned to normal after tumor resection. These data showed that IGF-II was partly dependent on GH and nutritional conditions and that IGF-II was the most likely cause of some cases of hypoglycemia with extrapancreatic tumor. This specific and sensitive RIA of IGF-II would be useful in evaluating its physiological and pathological role in plasma and tissue. PMID:2086202

  11. Igf2 ligand dependency of Pten(+/-) developmental and tumour phenotypes in the mouse.

    PubMed

    Church, D N; Phillips, B R; Stuckey, D J; Barnes, D J; Buffa, F M; Manek, S; Clarke, K; Harris, A L; Carter, E J; Hassan, A B

    2012-08-01

    The tumour suppressor PTEN is a key negative regulator of the PI3K-Akt pathway, and is frequently either reduced or lost in human tumours. Murine genetic studies have confirmed that reduction of Pten promotes tumourigenesis in multiple organs, and demonstrated dependency of tumour development on the activation of downstream components such as Akt. Insulin-like growth factors (IGFs) act via IGF1R to activate the PI3K-Akt pathway, and are commonly upregulated in cancer. A context-dependent interplay between IGFs and PTEN exists in normal tissue and tumours; increased IGF2 ligand supply induces Pten expression creating an autoregulatory negative feedback loop, whereas complete loss of PTEN may either cooperate with IGF overexpression in tumour promotion, or result in desensitisation to IGF ligand. However, it remains unknown whether neoplasia associated with Pten loss is dependent on upstream IGF ligand supply in vivo. We evaluated this by generation of Pten(+/-) mice with differing allelic dosage of Igf2, an imprinted gene encoding the potent embryonic and tumour growth factor Igf2. We show that biallelic Igf2 supply potentiates a previously unreported Pten(+/-) placental phenotype and results in strain-dependent cardiac hyperplasia and neonatal lethality. Importantly, we also show that the effects of Pten loss in vivo are modified by Igf2 supply, as lack of Igf2 results in extended survival and delayed tumour development while biallelic supply is associated with reduced lifespan and accelerated neoplasia in females. Furthermore, we demonstrate that reduction of PTEN protein to heterozygote levels in human MCF7 cells is associated with increased proliferation in response to IGF2, and does not result in desensitisation to IGF2 signalling. These data indicate that the effects of Pten loss at heterozygote levels commonly observed in human tumours are modified by Igf2 ligand, and emphasise the importance of the evaluation of upstream pathways in tumours with Pten loss

  12. Expression profile of IGF paralog genes in liver and muscle of a GH-transgenic zebrafish.

    PubMed

    Nornberg, Bruna Felix; Figueiredo, Marcio Azevedo; Marins, Luis Fernando

    2016-01-15

    The objective of this study was to investigate the relationship between IGFs produced in the liver and skeletal muscle with muscle hypertrophy previously observed in a line of GH-transgenic zebrafish. In this sense, we evaluated the expression of genes related to the IGF system in liver and muscle of transgenics, as well as the main intracellular signaling pathways used by GH/IGF axis. Our results showed an increase in expression of igf1a, igf2a, and igf2b genes in the liver. Moreover, there was a decrease in the expression of igf1ra and an increase in muscle igf2r of transgenics, indicating a negative response of muscle tissue with respect to excess circulating IGFs. Muscle IGFs expression analyses revealed a significant increase only for igf2b, accompanied by a parallel induction of igfbp5a gene. The presence of IGFBP5a may potentiate the IGF2 action in muscle cells differentiation. Regarding JAK/STAT-related genes, we observed an alteration in the expression profile of both stat3 and stat5a in transgenic fish liver. No changes were observed in the muscle, suggesting that both tissues respond differently to GH-transgenesis. Western blotting analyses indicated an imbalance between the phosphorylation levels of the proliferative (MEK/ERK) and hypertrophic (PI3K/Akt) pathways, in favor of the latter. In summary, the results of this study suggest that the hypertrophy caused by GH-transgenesis in zebrafish may be due to circulating IGFs produced by the liver, with an important participation of muscle IGF2b. This group of IGFs appears to be favoring the hypertrophic intracellular pathway in muscle tissue of transgenic zebrafish. PMID:26718079

  13. THE LOCAL EXPRESSION AND ABUNDANCE OF INSULIN-LIKE GROWTH FACTOR (IGF) BINDING PROTEINS IN SKELETAL MUSCLE ARE REGULATED BY AGE AND GENDER BUT NOT LOCAL IGF-I "IN VIVO"

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We wished to determine whether sustained IGF-I production in skeletal muscle increases local IGF binding protein (IGFBP) abundance, thereby mitigating the long-term stimulation of muscle growth by IGF-I. Muscle growth of transgenic mice that overexpress IGF-I in muscle (SIS2) and of wild-type (Wt) m...

  14. Regulation of insulin-like growth factor (IGF)-binding protein expression by growth factors and cytokines alters IGF-mediated proliferation of postnatal lung fibroblasts.

    PubMed

    Price, Wayne A

    2004-06-01

    Postnatal day 5 is the beginning of septation and the peak of postnatal fibroblast proliferation. The author and colleagues studied fibroblasts from this developmental time period to determine factors that regulate cell proliferation. Exposure of cells to insulin-like growth factor (IGF)-I for 48 hours increased cell number whereas exposure to epithelial growth factor (EGF), platelet-derived growth factor (PDGF)-BB, fibroblast growth factor (FGF)-7, FGF-2, tumor necrosis factor-alpha (TNF-alpha), or interleukin (L)-1beta did not alter cell number. Long[R3]IGF-I (a synthetic IGF analog with reduced affinity for IGF-binding proteins [IGFBPs]) was more potent than IGF-I, with half-maximal stimulation at a dose of 0.6 nM for long[R3]IGF-I compared to 1.5 nM for IGF-I, suggesting that IGFBPs in the conditioned medium (CM) inhibit IGF activity. Addition of exogenous IGFBP-3 inhibited the IGF-stimulated increase in cell number. Addition of IGFBP-4 did not alter IGF activity because IGF-I stimulated proteolysis of IGFBP-4. The expression of mRNA for PAPP-A (a known IGFBP-4 protease) suggests that the clearance of IGFBP-4 is mediated by pregnancy-associated plasma protein (PAPP)-A. Exposure of cells to TNF-alpha or IL-1beta increased IGFBP-3 mRNA abundance and IGFBP-3 protein in CM. PDGF-BB and IL-1beta increased IGFBP-4 protein abundance and PDGF-BB and dibutyryl cAMP increased IGFBP-4 mRNA. The increase in CM IGFBP-3 following TNF-alpha exposure blocked IGF-mediated cell proliferation, suggesting that the growth factor- and cytokine-mediated changes in IGFBP abundance regulate postnatal fibroblast cell proliferation. PMID:15204833

  15. Eighteen Insulin-like Growth Factor (IGF) pathway genes, circulating levels of IGF-1 and its binding protein (IGFBP-3), and risk of prostate and breast cancer

    PubMed Central

    Gu, Fangyi; Schumacher, Fredrick R.; Canzian, Federico; Allen, Naomi E.; Albanes, Demetrius; Berg, Christine D; Berndt, Sonja I.; Boeing, Heiner; Bueno-de-Mesquita, H. Bas; Buring, Julie E.; Chabbert-Buffet, Nathalie; Chanock, Stephen J.; Clavel-Chapelon, Françoise; Dumeaux, Vanessa; Gaziano, J. Michael; Giovannucci, Edward L.; Haiman, Christopher A.; Hankinson, Susan E.; Hayes, Richard B.; Henderson, Brian E.; Hunter, David J.; Hoover, Robert N.; Johansson, Mattias; Key, Timothy J.; Khaw, Kay-Tee; Kolonel, Laurence N.; Lagiou, Pagona; Lee, I-Min; LeMarchand, Loic; Lund, Eiliv; Ma, Jing; Onland-Moret, N. Charlotte; Overvad, Kim; Rodriguez, Laudina; Sacerdote, Carlotta; Sánchez, Maria-José; Stampfer, Meir J.; Stattin, Pär; Stram, Daniel O.; Thomas, Gilles; Thun, Michael J.; Tjønneland, Anne; Trichopoulos, Dimitrios; Tumino, Rosario; Virtamo, Jarmo; Weinstein, Stephanie J.; Willett, Walter C.; Yeager, Meredith; Zhang, Shumin M.; Kaaks, Rudolf; Riboli, Elio; Ziegler, Regina G.; Kraft, Peter

    2010-01-01

    Background Circulating levels of insulin-like growth factor I (IGF-1) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-1 and IGFBP-3 in studies of adult twins. Methods We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-1 and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNPs) were genotyped in over 5500 Caucasian men and 5500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium (BPC3). Results After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-1 (p<2.1×10−4); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R2=0.62% of the variation in circulating IGF-1 and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-1 or IGFBP-3 and risk of prostate or breast cancers. Conclusion Common genetic variation in the IGF1 and SSTR5 genes appears to influence circulating IGF-1 levels, and variation in IGFBP3 and IGFALS appears to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-1 and IGFBP-3 in Caucasian men and women. Impact Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes. PMID:20810604

  16. Phylogenetic footprint analysis of IGF2 in extant mammals.

    PubMed

    Weidman, Jennifer R; Murphy, Susan K; Nolan, Catherine M; Dietrich, Fred S; Jirtle, Randy L

    2004-09-01

    Genomic imprinting results in monoallelic gene transcription that is directed by cis-acting regulatory elements epigenetically marked in a parent-of-origin-dependent manner. We performed phylogenetic sequence and epigenetic comparisons of IGF2 between the nonimprinted platypus (Ornithorhynchus anatinus) and imprinted opossum (Didelphis virginiana), mouse (Mus musculus), and human (Homo sapiens) to determine if their divergent imprint status would reflect differences in the conservation of genomic elements important in the regulation of imprinting. We report herein that IGF2 imprinting does not correlate evolutionarily with differential intragenic methylation, nor is it associated with motif 13, a reported IGF2-specific "imprint signature" located in the coding region. Instead, IGF2 imprinting is strongly associated with both the lack of short interspersed transposable elements (SINEs) and an intragenic conserved inverted repeat that contains candidate CTCF-binding sites, a role not previously ascribed to this particular sequence element. Our results are the first to demonstrate that comparative footprint analysis of species from evolutionarily distant mammalian clades, and exhibiting divergent imprint status is a powerful bioinformatics-based approach for identifying cis-acting elements potentially involved not only in the origins of genomic imprinting, but also in its maintenance in humans. PMID:15342558

  17. Higher Hepatic miR-29 Expression in Undernourished Male Rats During the Postnatal Period Targets the Long-Term Repression of IGF-1.

    PubMed

    Sohi, Gurjeev; Revesz, Andrew; Ramkumar, Julie; Hardy, Daniel B

    2015-09-01

    A nutritional mismatch in postnatal life of low birth weight offspring increases the risk of developing the metabolic syndrome. Moreover, this is associated with decreased hepatic Igf1 expression, leading to impaired growth and metabolism. Previously, we have demonstrated that the timing of nutritional restoration in perinatal life can differentially program hepatic gene expression. Although microRNAs also play an important role in silencing gene expression, to date, the impact of a nutritional mismatch in neonatal life on their long-term expression has not been evaluated. Given the complementarity of miR-29 to the 3' untranslated region of Igf1, we examined how protein restoration in maternal protein restriction rat offspring influences hepatic miR-29 and Igf1 expression in adulthood. Pregnant Wistar rats were designated into 1 of 4 dietary regimes: 20% protein (control), 8% protein during lactation only (LP-Lact), 8% protein during gestation only (LP1) or both (LP2). The steady-state expression of hepatic miR-29 mRNA significantly increased in LP2 offspring at postnatal day 21 and 130, and this was inversely related to hepatic Igf1 mRNA and body weight. Interestingly, this reciprocal association was stronger in LP-Lact offspring at postnatal day 21. Functional relevance of this in vivo relationship was evaluated by transfection of miR-29 mimics in neonatal Clone 9 rat hepatoma cells. Transfection with miR-29 suppressed Igf1 expression by 12 hours. Collectively, these findings implicate that nutritional restoration after weaning (post liver differentiation) in maternal protein restriction rat offspring fails to prevent long-term impaired growth, in part, due to miR-29 suppression of hepatic Igf1 expression. PMID:26151354

  18. Differential effects of insulin-like growth factor I (IGF-I) and IGF-binding protein-1 on protein metabolism in human skeletal muscle cells.

    PubMed

    Frost, R A; Lang, C H

    1999-09-01

    Insulin-like growth factor-binding protein-1 (BP-1) is a multifunctional protein that binds IGF-I in solution and integrins on the cell surface. BP-1 is overexpressed during catabolic illnesses, and the protein accumulates in skeletal muscle. To define a potential physiological role for BP-1 in regulating muscle protein balance, we have examined the effect of IGF-I and BP-1 on protein synthesis and degradation in human skeletal muscle cells. IGF-I-stimulated protein synthesis by 20%, and this was completely inhibited by either phosphorylated or nonphosphorylated BP-1. Half-maximal inhibition of protein synthesis occurred at a molar ratio of BP-1 to IGF-I of 1.5:1. BP-1 failed to form a complex with a truncated form of IGF-I (desIGF-I), and consequently, BP-1 failed to inhibit the ability of desIGF-I to stimulate protein synthesis. IGF-I and BP-1 dose-dependently inhibited protein degradation individually, and both BP-1 phosphovariants failed to block the ability of IGF-I to do the same. Blocking integrin receptor occupancy with the integrin antagonist echistatin blunted the ability of BP-1 to inhibit protein degradation, but had no significant effect on IGF-I-mediated changes in protein synthesis or degradation. The extracellular matrix protein vitronectin also inhibited protein degradation, but vitronectin receptor antibodies failed to block BP-1 action. In contrast, antibodies to the beta1 integrin subunit blocked BP-1-mediated inhibition of protein degradation. Rapamycin inhibited IGF-I-dependent protein synthesis, but not the ability of IGF-I to inhibit proteolysis. In contrast, rapamycin completely blocked the ability of BP-1 to inhibit proteolysis. Our results demonstrate that BP-1 inhibits IGF-I-mediated protein synthesis by binding to IGF-I. BP-1, acting independently of IGF-I, inhibits protein degradation. The IGF-independent response occurs via beta1 integrin binding and stimulation of a rapamycin-sensitive signal transduction pathway. PMID:10465265

  19. Long [R3] insulin-like growth factor-I reduces growth, plasma growth hormone, IGF binding protein-3 and endogenous IGF-I concentrations in pigs.

    PubMed

    Dunaiski, V; Dunshea, F R; Walton, P E; Goddard, C

    1997-12-01

    Growth hormone (GH) improves growth performance in the pig. Analogues of insulin-like growth factor-I (IGF-I) that bind poorly to IGF binding proteins (IGFBP) stimulate growth in the rat but, in contrast, inhibit growth in the pig. This study was designed to determine the effect of IGF peptides alone or in combination with porcine GH (pGH) on growth characteristics and plasma hormone concentrations in finisher pigs. A four-day infusion of Long [R3] IGF-I (LR3IGF-I; 180 micrograms/kg/day) decreased the average daily gain, food intake, and plasma IGFBP-3, IGF-I and insulin concentrations. The mean plasma GH concentration was decreased by 23% and the area under the GH peaks was reduced by 60%. Co-administration of pGH (30 micrograms/kg/day) with LR3IGF-I had no interactive effect on growth performance, and plasma insulin, IGFBP-3 and IGF-I concentrations remained suppressed. The area under the GH peaks was not restored with this combination treatment although mean plasma GH concentrations were elevated in all animals receiving pGH. Infusion of IGF-I (180 micrograms/kg/day) decreased plasma insulin and mean GH concentrations but had no significant effect on IGFBP-3 concentrations. Average daily gain and feed intake were not changed by IGF-I treatment. A combination of IGF-I and pGH injection (30 micrograms/kg/day) increased plasma IGFBP-3 concentrations but plasma insulin levels remained suppressed. Plasma glucose levels were unaffected by any treatment. The study demonstrates that both IGF-I and LR3IGF-I suppress plasma GH concentrations in finisher pigs. This, in turn, may be responsible for the reduction in the plasma concentration of IGF-I, IGFBP-3 and insulin seen in LR3IGF-I-treated animals. The decrease in these parameters may contribute to the inhibitory effect of LR3IGF-I on growth performance in the pig. PMID:9488001

  20. The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis[S

    PubMed Central

    Laggai, Stephan; Kessler, Sonja M.; Boettcher, Stefan; Lebrun, Valérie; Gemperlein, Katja; Lederer, Eva; Leclercq, Isabelle A.; Mueller, Rolf; Hartmann, Rolf W.; Haybaeck, Johannes; Kiemer, Alexandra K.

    2014-01-01

    Liver-specific overexpression of the insulin-like growth factor 2 (IGF2) mRNA binding protein p62/IGF2BP2-2 induces a fatty liver, which highly expresses IGF2. Because IGF2 expression is elevated in patients with steatohepatitis, the aim of our study was to elucidate the role and interconnection of p62 and IGF2 in lipid metabolism. Expression of p62 and IGF2 highly correlated in human liver disease. p62 induced an elevated ratio of C18:C16 and increased fatty acid elongase 6 (ELOVL6) protein, the enzyme catalyzing the elongation of C16 to C18 fatty acids and promoting nonalcoholic steatohepatitis in mice and humans. The p62 overexpression induced the activation of the ELOVL6 transcriptional activator sterol regulatory element binding transcription factor 1 (SREBF1). Recombinant IGF2 induced the nuclear translocation of SREBF1 and a neutralizing IGF2 antibody reduced ELOVL6 and mature SREBF1 protein levels. Concordantly, p62 and IGF2 correlated with ELOVL6 in human livers. Decreased palmitoyl-CoA levels, as found in p62 transgenic livers, can explain the lipogenic action of ELOVL6. Accordingly, p62 represents an inducer of hepatic C18 fatty acid production via a SREBF1-dependent induction of ELOVL6. These findings underline the detrimental role of p62 in liver disease. PMID:24755648

  1. Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The insulin-like growth factor-1 (IGF-1) signaling axis is important for cell growth, differentiation, and survival, and increased serum IGF is a risk factor for prostate and other cancers. To study IGF-1 action on the prostate, we created transgenic (PB-Des) mice that specifically express human IGF...

  2. The role of IGFs in the regulation of ovarian follicular growth in the brushtail possum (Trichosurus vulpecula).

    PubMed

    Juengel, Jennifer L; Haydon, Lisa J; Mester, Brigitta; Thomson, Brian P; Beaumont, Michael; Eckery, Douglas C

    2010-08-01

    IGFs are known to be key regulators of ovarian follicular growth in eutherian mammals, but little is known regarding their role in marsupials. To better understand the potential role of IGFs in the regulation of follicular growth in marsupials, expression of mRNAs encoding IGF1, IGF2, IGF1R, IGF-binding protein 2 (IGFBP2), IGFBP4 and IGFBP5 was localized by in situ hybridization in developing ovarian follicles of the brushtail possum. In addition, the effects of IGF1 and IGF2 on granulosa cell function were tested in vitro. Both granulosa and theca cells synthesize IGF mRNAs, with the theca expressing IGF1 mRNA and granulosa cell expressing IGF2 mRNA. Oocytes and granulosa cells express IGF1R. Granulosa and theca cells expressed IGFBP mRNAs, although the pattern of expression differed between the BPs. IGFBP5 mRNA was differentially expressed as the follicles developed with granulosa cells of antral follicles no longer expressing IGFBP5 mRNA, suggesting an increased IGF bioavailability in the antral follicle. The IGFBP protease, PAPPA mRNA, was also expressed in granulosa cells of growing follicles. Both IGF1 and IGF2 stimulated thymidine incorporation but had no effect on progesterone production. Thus, IGF may be an important regulator of ovarian follicular development in marsupials as has been shown in eutherian mammals. PMID:20522481

  3. IGF-1 Has Plaque-Stabilizing Effects in Atherosclerosis by Altering Vascular Smooth Muscle Cell Phenotype

    PubMed Central

    von der Thüsen, Jan H.; Borensztajn, Keren S.; Moimas, Silvia; van Heiningen, Sandra; Teeling, Peter; van Berkel, Theo J.C.; Biessen, Erik A.L.

    2011-01-01

    Insulin-like growth factor-1 (IGF-1) signaling is important for the maintenance of plaque stability in atherosclerosis due to its effects on vascular smooth muscle cell (vSMC) phenotype. To investigate this hypothesis, we studied the effects of the highly inflammatory milieu of the atherosclerotic plaque on IGF-1 signaling and stability-related phenotypic parameters of murine vSMCs in vitro, and the effects of IGF-1 supplementation on plaque phenotype in an atherosclerotic mouse model. M1-polarized, macrophage-conditioned medium inhibited IGF-1 signaling by ablating IGF-1 and increasing IGF-binding protein 3, increased vSMC apoptosis, and decreased proliferation. Expression of α-actin and col3a1 genes was strongly attenuated by macrophage-conditioned medium, whereas expression of matrix-degrading enzymes was increased. Importantly, all of these effects could be corrected by supplementation with IGF-1. In vivo, treatment with the stable IGF-1 analog Long R3 IGF-1 in apolipoprotein E knockout mice reduced stenosis and core size, and doubled cap/core ratio in early atherosclerosis. In advanced plaques, Long R3 IGF-1 increased the vSMC content of the plaque by more than twofold and significantly reduced the rate of intraplaque hemorrhage. We believe that IGF-1 in atherosclerotic plaques may have a role in preventing plaque instability, not only by modulating smooth muscle cell turnover, but also by altering smooth muscle cell phenotype. PMID:21281823

  4. IGF-1 has plaque-stabilizing effects in atherosclerosis by altering vascular smooth muscle cell phenotype.

    PubMed

    von der Thüsen, Jan H; Borensztajn, Keren S; Moimas, Silvia; van Heiningen, Sandra; Teeling, Peter; van Berkel, Theo J C; Biessen, Erik A L

    2011-02-01

    Insulin-like growth factor-1 (IGF-1) signaling is important for the maintenance of plaque stability in atherosclerosis due to its effects on vascular smooth muscle cell (vSMC) phenotype. To investigate this hypothesis, we studied the effects of the highly inflammatory milieu of the atherosclerotic plaque on IGF-1 signaling and stability-related phenotypic parameters of murine vSMCs in vitro, and the effects of IGF-1 supplementation on plaque phenotype in an atherosclerotic mouse model. M1-polarized, macrophage-conditioned medium inhibited IGF-1 signaling by ablating IGF-1 and increasing IGF-binding protein 3, increased vSMC apoptosis, and decreased proliferation. Expression of α-actin and col3a1 genes was strongly attenuated by macrophage-conditioned medium, whereas expression of matrix-degrading enzymes was increased. Importantly, all of these effects could be corrected by supplementation with IGF-1. In vivo, treatment with the stable IGF-1 analog Long R3 IGF-1 in apolipoprotein E knockout mice reduced stenosis and core size, and doubled cap/core ratio in early atherosclerosis. In advanced plaques, Long R3 IGF-1 increased the vSMC content of the plaque by more than twofold and significantly reduced the rate of intraplaque hemorrhage. We believe that IGF-1 in atherosclerotic plaques may have a role in preventing plaque instability, not only by modulating smooth muscle cell turnover, but also by altering smooth muscle cell phenotype. PMID:21281823

  5. IGF2BP3 modulates the interaction of invasion-associated transcripts with RISC

    PubMed Central

    Ennajdaoui, Hanane; Howard, Jonathan M.; Sterne-Weiler, Timothy; Jahanbani, Fereshteh; Coyne, Doyle J.; Uren, Philip J.; Dargyte, Marija; Katzman, Sol; Draper, Jolene M.; Wallace, Andrew; Cazarez, Oscar; Burns, Suzanne C.; Qiao, Mei; Hinck, Lindsay; Smith, Andrew D.; Toloue, Masoud M.; Blencowe, Benjamin J.; Penalva, Luiz O.F.; Sanford, Jeremy R.

    2016-01-01

    Summary Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) expression correlates with malignancy. But its role(s) in pathogenesis remain enigmatic. Here, we interrogated the IGF2BP3-RNA interaction network in pancreatic ductal adenocarcinoma (PDAC) cells. Using a combination of genome-wide approaches we identify 164 direct mRNA targets of IGF2BP3. These transcripts encode proteins enriched for functions such as cell migration, proliferation and adhesion. Loss of IGF2BP3 reduced PDAC cell invasiveness and remodeled focal adhesion junctions. Individual-nucleotide resolution crosslinking immunoprecipitation (iCLIP) revealed significant overlap of IGF2BP3 and miRNA binding sites. IGF2BP3 promotes association of the RNA induced silencing complex (RISC) with specific transcripts. Our results show that IGF2BP3 influences a malignancy-associated RNA regulon by modulating miRNA-mRNA interactions. PMID:27210763

  6. IGF2BP3 Modulates the Interaction of Invasion-Associated Transcripts with RISC.

    PubMed

    Ennajdaoui, Hanane; Howard, Jonathan M; Sterne-Weiler, Timothy; Jahanbani, Fereshteh; Coyne, Doyle J; Uren, Philip J; Dargyte, Marija; Katzman, Sol; Draper, Jolene M; Wallace, Andrew; Cazarez, Oscar; Burns, Suzanne C; Qiao, Mei; Hinck, Lindsay; Smith, Andrew D; Toloue, Masoud M; Blencowe, Benjamin J; Penalva, Luiz O F; Sanford, Jeremy R

    2016-05-31

    Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) expression correlates with malignancy, but its role(s) in pathogenesis remains enigmatic. We interrogated the IGF2BP3-RNA interaction network in pancreatic ductal adenocarcinoma (PDAC) cells. Using a combination of genome-wide approaches, we have identified 164 direct mRNA targets of IGF2BP3. These transcripts encode proteins enriched for functions such as cell migration, proliferation, and adhesion. Loss of IGF2BP3 reduced PDAC cell invasiveness and remodeled focal adhesion junctions. Individual nucleotide resolution crosslinking immunoprecipitation (iCLIP) revealed significant overlap of IGF2BP3 and microRNA (miRNA) binding sites. IGF2BP3 promotes association of the RNA-induced silencing complex (RISC) with specific transcripts. Our results show that IGF2BP3 influences a malignancy-associated RNA regulon by modulating miRNA-mRNA interactions. PMID:27210763

  7. Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas.

    PubMed

    Creemers, S G; van Koetsveld, P M; van Kemenade, F J; Papathomas, T G; Franssen, G J H; Dogan, F; Eekhoff, E M W; van der Valk, P; de Herder, W W; Janssen, J A M J L; Feelders, R A; Hofland, L J

    2016-09-01

    Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Discrimination of ACCs from adrenocortical adenomas (ACAs) is challenging on both imaging and histopathological grounds. High IGF2 expression is associated with malignancy, but shows large variability. In this study, we investigate whether specific methylation patterns of IGF2 regulatory regions could serve as a valuable biomarker in distinguishing ACCs from ACAs. Pyrosequencing was used to analyse methylation percentages in DMR0, DMR2, imprinting control region (ICR) (consisting of CTCF3 and CTCF6) and the H19 promoter. Expression of IGF2 and H19 mRNA was assessed by real-time quantitative PCR. Analyses were performed in 24 ACCs, 14 ACAs and 11 normal adrenals. Using receiver operating characteristic (ROC) analysis, we evaluated which regions showed the best predictive value for diagnosis of ACC and determined the diagnostic accuracy of these regions. In ACCs, the DMR0, CTCF3, CTCF6 and the H19 promoter were positively correlated with IGF2 mRNA expression (P<0.05). Methylation in the most discriminating regions distinguished ACCs from ACAs with a sensitivity of 96%, specificity of 100% and an area under the curve (AUC) of 0.997±0.005. Our findings were validated in an independent cohort of 9 ACCs and 13 ACAs, resulting in a sensitivity of 89% and a specificity of 92%. Thus, methylation patterns of IGF2 regulatory regions can discriminate ACCs from ACAs with high diagnostic accuracy. This proposed test may become the first objective diagnostic tool to assess malignancy in adrenal tumours and facilitate the choice of therapeutic strategies in this group of patients. PMID:27535174

  8. The association between IGF-1 polymorphisms and high myopia

    PubMed Central

    Zhang, Xiaoyu; Zhou, Xingtao; Qu, Xinhua

    2015-01-01

    Background: The potential association between IGF-1 polymorphisms and high myopia has been investigated in previous studies, but the actual relationship remains controversial. Accordingly, we conducted a meta-analysisincludingcase-control and cohort studies to assess the existing relationship between high myopia and IGF-1 polymorphisms. We searched MEDLINE, EMBASE, and OVID. Odds ratios (OR) with 95% confidence intervals (CI) were derived for single-nucleotide polymorphisms (SNPs) involved in the studies obtained from the retrospective database search. Analyses of heterogeneity, sensitivity, and publication bias were also conducted. The findings from this meta-analysis were based on approximately 2,187 high myopia cases and 1,183 controls, and were used to assess the association between three IGF-1 genetic polymorphisms (rs6214, rs12423791, and rs5742632) and high myopia risks. We investigated the association of the IGF-1 gene SNP rs6214, but no statistical association was observed in the resulting odds ratios (OR) in the allelic (OR = 1.06, 95% CI = 0.89-1.25), dominant (OR = 1.07, 95% CI = 0.90-1.27), or recessive models (OR = 1.06, 95% CI = 0.89-1.26), or in the homozygote (OR = 1.12, 95% CI = 0.91-1.38) and heterozygote comparisons (OR = 1.06, 95% CI = 0.88-1.27). Simultaneously, two other selected SNPs, rs12423791 and rs5742632, were also studied, but similarly, no statistical association existed between these polymorphisms and the risk of high myopia. In conclusions, no statistical association between IGF-1 polymorphisms (rs6214, rs12423791, and rs5742632) and the risk of high myopia was observed following the reported meta-analysis. PMID:26309715

  9. Comments on: Chari, R.; Burke, T.A.; White, R.H.; Fox, M.A. Integrating Susceptibility into Environmental Policy: An Analysis of the National Ambient Air Quality Standard for Lead. Int. J. Environ. Res. Public Health 2012, 9, 1077–1096

    PubMed Central

    Bowers, Teresa S.

    2013-01-01

    A recent publication in International Journal of Environmental Research and Public Health by Chari et al. [1] provides no basis for changing the National Ambient Air Quality Standard (NAAQS) for lead in the U.S. to protect children in low socio-economic (SES) populations. The studies selected by Chari et al. for analysis do not provide comparable information on regression coefficients for the blood lead level-IQ relationship. The coefficients differ from one another more on the basis of unequal blood lead metrics, ages of blood lead measurement, and differences in covariate adjustments and standardization, than the difference postulated by Chari et al. to correspond to low vs. high SES populations. PMID:23429754

  10. Disrupted TSH Receptor Expression in Female Mouse Lung Fibroblasts Alters Subcellular IGF-1 Receptor Distribution.

    PubMed

    Atkins, Stephen J; Lentz, Stephen I; Fernando, Roshini; Smith, Terry J

    2015-12-01

    A relationship between the actions of TSH and IGF-1 was first recognized several decades ago. The close physical and functional associations between their respective receptors (TSHR and IGF-1R) has been described more recently in thyroid epithelium and human orbital fibroblasts as has the noncanonical behavior of IGF-1R. Here we report studies conducted in lung fibroblasts from female wild-type C57/B6 (TSHR(+/+)) mice and their littermates in which TSHR has been knocked out (TSHR(-/-)). Flow cytometric analysis revealed that cell surface IGF-1R levels are substantially lower in TSHR(-/-) fibroblasts compared with TSHR(+/+) fibroblasts. Confocal immunofluorescence microscopy revealed similar divergence with regard to both cytoplasmic and nuclear IGF-1R. Western blot analysis demonstrated both intact IGF-1R and receptor fragments in both cellular compartments. In contrast, IGF-1R mRNA levels were similar in fibroblasts from mice without and with intact TSHR expression. IGF-1 treatment of TSHR(+/+) fibroblasts resulted in reduced nuclear and cytoplasmic staining for IGF-1Rα, whereas it enhanced the nuclear signal in TSHR(-/-) cells. In contrast, IGF-1 enhanced cytoplasmic IGF-1Rβ in TSHR(-/-) fibroblasts while increasing the nuclear signal in TSHR(+/+) cells. These findings indicate the intimate relationship between TSHR and IGF-1R found earlier in human orbital fibroblasts also exists in mouse lung fibroblasts. Furthermore, the presence of TSHR in these fibroblasts influenced not only the levels of IGF-1R protein but also its subcellular distribution and response to IGF-1. They suggest that the mouse might serve as a suitable model for delineating the molecular mechanisms overarching these two receptors. PMID:26389690

  11. Fsh Stimulates Spermatogonial Proliferation and Differentiation in Zebrafish via Igf3.

    PubMed

    Nóbrega, Rafael Henrique; Morais, Roberto Daltro Vidal de Souza; Crespo, Diego; de Waal, Paul P; de França, Luiz Renato; Schulz, Rüdiger W; Bogerd, Jan

    2015-10-01

    Growth factors modulate germ line stem cell self-renewal and differentiation behavior. We investigate the effects of Igf3, a fish-specific member of the igf family. Fsh increased in a steroid-independent manner the number and mitotic index of single type A undifferentiated spermatogonia and of clones of type A differentiating spermatogonia in adult zebrafish testis. All 4 igf gene family members in zebrafish are expressed in the testis but in tissue culture only igf3 transcript levels increased in response to recombinant zebrafish Fsh. This occurred in a cAMP/protein kinase A-dependent manner, in line with the results of studies on the igf3 gene promoter. Igf3 protein was detected in Sertoli cells. Recombinant zebrafish Igf3 increased the mitotic index of type A undifferentiated and type A differentiating spermatogonia and up-regulated the expression of genes related to spermatogonial differentiation and entry into meiosis, but Igf3 did not modulate testicular androgen release. An Igf receptor inhibitor blocked these effects of Igf3. Importantly, the Igf receptor inhibitor also blocked Fsh-induced spermatogonial proliferation. We conclude that Fsh stimulated Sertoli cell production of Igf3, which promoted via Igf receptor signaling spermatogonial proliferation and differentiation and their entry into meiosis. Because previous work showed that Fsh also released spermatogonia from an inhibitory signal by down-regulating anti-Müllerian hormone and by stimulating androgen production, we can now present a model, in which Fsh orchestrates the activity of stimulatory (Igf3, androgens) and inhibitory (anti-Müllerian hormone) signals to promote spermatogenesis. PMID:26207345

  12. Preclinical screening for retinopathy of prematurity risk using IGF1 levels at 3 weeks post-partum.

    PubMed

    Pérez-Muñuzuri, Alejandro; Couce-Pico, Maria Luz; Baña-Souto, Ana; López-Suárez, Olalla; Iglesias-Deus, Alicia; Blanco-Teijeiro, José; Fernández-Lorenzo, José Ramón; Fraga-Bermúdez, José María

    2014-01-01

    Following current recommendations for preventing retinopathy of prematurity (ROP) involves screening a large number of patients. We performed a prospective study to establish a useful screening system for ROP prediction and we have determined that measuring serum levels of IGF1 at week three and the presence of sepsis have a high predictive value for the subsequent development of ROP. A total of 145 premature newborn, with birthweight <1500 g and/or <32 weeks gestational age, were enrolled. 26.9% of them showed some form of retinopathy. A significant association was found between the development of retinopathy and each of the following variables: early gestational age, low birthweight, requiring mechanical ventilation, oxygen treatment, intracranial haemorrhage, sepsis during the first three weeks, bronchopulmonary dysplasia, the need for erythrocyte transfusion, erythropoietin treatment, and low levels of serum IGF1 in the third week. A multiple logistic regression analysis was used to obtain curves for the probability of developing ROP, based on the main factors linked with ROP, namely serum levels of IGF1 and presence of sepsis. Such preclinical screening has the ability to identify patients with high-risk of developing retinopathy and should lead to better prediction for ROP, while at the same time optimising the use of clinical resources, both human and material. PMID:24523937

  13. Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2.

    PubMed

    Kwon, Young; Song, Wei; Droujinine, Ilia A; Hu, Yanhui; Asara, John M; Perrimon, Norbert

    2015-04-01

    Organ wasting, related to changes in nutrition and metabolic activity of cells and tissues, is observed under conditions of starvation and in the context of diseases, including cancers. We have developed a model for organ wasting in adult Drosophila, whereby overproliferation induced by activation of Yorkie, the Yap1 oncogene ortholog, in intestinal stem cells leads to wasting of the ovary, fat body, and muscle. These organ-wasting phenotypes are associated with a reduction in systemic insulin/IGF signaling due to increased expression of the secreted insulin/IGF antagonist ImpL2 from the overproliferating gut. Strikingly, expression of rate-limiting glycolytic enzymes and central components of the insulin/IGF pathway is upregulated with activation of Yorkie in the gut, which may provide a mechanism for this overproliferating tissue to evade the effect of ImpL2. Altogether, our study provides insights into the mechanisms underlying organ-wasting phenotypes in Drosophila and how overproliferating tissues adapt to global changes in metabolism. PMID:25850671

  14. Minireview: The Complexities of IGF/Insulin Signaling in Aging: Why Flies and Worms Are Not Humans.

    PubMed

    Sell, Christian

    2015-08-01

    A remarkable plasticity in life span has been uncovered in recent years, offering hope that the basic mechanisms of aging and interventions that delay aging may be identified in the coming decades. Life span extension has been achieved by genetic manipulation in multiple organisms including Sarcomyces cervisae, Caenorhabditis elegans, and Drosophila melanogaster, resulting in more than a doubling of life span in some cases. Typically, a reduction in function has been the most effective approach to extending life span, and a reduction in the insulin/IGF-1 signaling pathway appears to provide the most robust increase in life span. This highly conserved pathway integrates growth/survival signals with nutrient status. In mammals, it comprises part of the neuroendocrine axis, a critical regulator of growth and development. Reduced functionality of the neuroendocrine axis itself promotes life span extension in mammals; however, reduced activity of the IGF-1 signaling pathway specifically leads to less robust increases in life span. This review examines the differences in the insulin/IGF-1 axis between invertebrate and mammalian systems and discusses implications of these differences in terms of life span modulation. PMID:26102060

  15. Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice

    PubMed Central

    Csiszar, Anna; Labinskyy, Nazar; Perez, Viviana; Recchia, Fabio A.; Podlutsky, Andrej; Mukhopadhyay, Partha; Losonczy, Gyorgy; Pacher, Pal; Austad, Steven N.; Bartke, Andrzej; Ungvari, Zoltan

    2008-01-01

    Hypopituitary Ames dwarf mice have low circulating growth hormone (GH)/IGF-I levels, and they have extended longevity and exhibit many symptoms of delayed aging. To elucidate the vascular consequences of Ames dwarfism we compared endothelial O2•− and H2O2 production, mitochondrial reactive oxygen species (ROS) generation, expression of antioxidant enzymes, and nitric oxide (NO) production in aortas of Ames dwarf and wild-type control mice. In Ames dwarf aortas endothelial O2•− and H2O2 production and ROS generation by mitochondria were enhanced compared with those in vessels of wild-type mice. In Ames dwarf aortas there was a less abundant expression of Mn-SOD, Cu,Zn-SOD, glutathione peroxidase (GPx)-1, and endothelial nitric oxide synthase (eNOS). NO production and acetylcholine-induced relaxation were also decreased in aortas of Ames dwarf mice. In cultured wild-type mouse aortas and in human coronary arterial endothelial cells treatment with GH and IGF significantly reduced cellular O2•− and H2O2 production and ROS generation by mitochondria and upregulated expression of Mn-SOD, Cu,Zn-SOD, GPx-1, and eNOS. Thus GH and IGF-I promote antioxidant phenotypic changes in the endothelial cells, whereas Ames dwarfism leads to vascular oxidative stress. PMID:18757483

  16. Minireview: The Complexities of IGF/Insulin Signaling in Aging: Why Flies and Worms Are Not Humans

    PubMed Central

    2015-01-01

    A remarkable plasticity in life span has been uncovered in recent years, offering hope that the basic mechanisms of aging and interventions that delay aging may be identified in the coming decades. Life span extension has been achieved by genetic manipulation in multiple organisms including Sarcomyces cervisae, Caenorhabditis elegans, and Drosophila melanogaster, resulting in more than a doubling of life span in some cases. Typically, a reduction in function has been the most effective approach to extending life span, and a reduction in the insulin/IGF-1 signaling pathway appears to provide the most robust increase in life span. This highly conserved pathway integrates growth/survival signals with nutrient status. In mammals, it comprises part of the neuroendocrine axis, a critical regulator of growth and development. Reduced functionality of the neuroendocrine axis itself promotes life span extension in mammals; however, reduced activity of the IGF-1 signaling pathway specifically leads to less robust increases in life span. This review examines the differences in the insulin/IGF-1 axis between invertebrate and mammalian systems and discusses implications of these differences in terms of life span modulation. PMID:26102060

  17. Potency of Full- Length MGF to Induce Maximal Activation of the IGF-I R Is Similar to Recombinant Human IGF-I at High Equimolar Concentrations

    PubMed Central

    Janssen, Joseph A. M. J. L.; Hofland, Leo J.; Strasburger, Christian J.; van den Dungen, Elisabeth S. R.; Thevis, Mario

    2016-01-01

    Aims To compare full-length mechano growth factor (full-length MGF) with human recombinant insulin-like growth factor-I (IGF-I) and human recombinant insulin (HI) in their ability to activate the human IGF-I receptor (IGF-IR), the human insulin receptor (IR-A) and the human insulin receptor-B (IR-B), respectively. In addition, we tested the stimulatory activity of human MGF and its stabilized analog Goldspink-MGF on the IGF-IR. Methods The effects of full-length MGF, IGF-I, human mechano growth factor (MGF), Goldspink-MGF and HI were compared using kinase specific receptor activation (KIRA) bioassays specific for IGF-I, IR-A or IR-B, respectively. These assays quantify activity by measuring auto-phosphorylation of the receptor upon ligand binding. Results IGF-IR: At high equimolar concentrations maximal IGF-IR stimulating effects generated by full-length MGF were similar to that of IGF-I (89-fold vs. 77-fold, respectively). However, EC50 values of IGF-I and full-length MGF for the IGF-I receptor were 0.86 nmol/L (95% CI 0.69–1.07) and 7.83 nmol/L (95% CI: 4.87–12.58), respectively. No IGF-IR activation was observed by human MGF and Goldspink-MGF, respectively. IR-A/IR-B: At high equimolar concentrations similar maximal IR-A stimulating effects were observed for full -length MGF and HI, but maximal IR-B stimulation achieved by full -length MGF was stronger than that by HI (292-fold vs. 98-fold). EC50 values of HI and full-length MGF for the IR-A were 1.13 nmol/L (95% CI 0.69–1.84) and 73.11 nmol/L (42.87–124.69), respectively; for IR-B these values were 1.28 nmol/L (95% CI 0.64–2.57) and 35.10 nmol/L (95% 17.52–70.33), respectively. Conclusions Full-length MGF directly stimulates the IGF-IR. Despite a higher EC50 concentration, at high equimolar concentrations full-length MGF showed a similar maximal potency to activate the IGF-IR as compared to IGF-I. Further research is needed to understand the actions of full-length MGF in vivo and to define the

  18. IGF-IR Signal Transduction Protein Content and Its Activation by IGF-I in Human Placentas: Relationship with Gestational Age and Birth Weight

    PubMed Central

    Iñiguez, Germán; Castro, Juan José; Garcia, Mirna; Kakarieka, Elena; Johnson, M. Cecilia; Cassorla, Fernando; Mericq, Verónica

    2014-01-01

    Introduction The human placenta expresses the IGF-I and IGF-IR proteins and their intracellular signal components (IRS-1, AKT and mTOR). The aim of this study was to assess the IGF-IR content and activation of downstream signaling molecules in placentas from newborns who were classified by gestational age and birth weight. We studied placentas from 25 term appropriate (T-AGA), 26 term small (T-SGA), 22 preterm AGA (PT-AGA), and 20 preterm SGA (PT-SGA) newborns. The total and phosphorylated IGF-IR, IRS-1, AKT, and mTOR contents were determined by Western Blot and normalized by actin or with their respective total content. The effect of IGF-I was determined by stimulating placental explants with recombinant IGF-I 10-8 mol/L for 15, 30, and 60 minutes. Results The IGF-IR content was higher in T-SGA compared to T-AGA placentas, and the IRS-1 content was higher in PT-placentas compared with their respective T-placentas. The effect of IGF-I on the phosphorylated forms of IGF-IR was increased in T-SGA (150%) and PT-SGA (300%) compared with their respective AGA placentas. In addition, AKT serine phosphorylation was higher in PT-SGA compared to PT-AGA and T-SGA placentas (90% and 390% respectively). Conclusion The higher protein content and response to IGF-I of IGF-IR, IRS-1, and AKT observed in SGA placentas may represent a compensatory mechanism in response to fetal growth restriction. PMID:25050889

  19. Insulin-like growth factors (IGFs) stimulate the release of alpha 1-antichymotrypsin and soluble IGF-II/mannose 6-phosphate receptor from MCF7 breast cancer cells.

    PubMed

    Confort, C; Rochefort, H; Vignon, F

    1995-09-01

    The growth of hormone-responsive MCF7 human breast cancer cells is controlled by steroid hormones and growth factors. By metabolic labeling of cells grown in steroid- and growth factor-stripped serum conditions, we show that insulin-like growth factors (IGF-I and IGF-II) increase by approximately 5-fold the release of several proteins including cathepsin D, alpha 1-antichymotrypsin, and soluble forms of the multifunctional IGF-II/mannose 6-phosphate (M6P) receptor. Two soluble forms of IGF-II/M6P receptors were detected, one major (approximately 260 kilodaltons) and one minor (approximately 85 kilodaltons) that probably represents a proteolytic fragment of the larger soluble molecule. IGFs increased receptor release in a dose-dependent fashion with 50-60% of newly synthesized receptor released at 5-10 nM IGFs. The release of IGF-II/M6P receptors correlated with the levels of secreted cathepsin D in different human breast cancer cells or in rats stable transfectants that are constitutively expressing variable levels of human cathepsin D. IGFs had a stronger effect on IGF-II/M6P receptor release, whereas estradiol treatment preferentially enhanced the release of protease and antiprotease. We thus demonstrate that in human breast cancer cells, IGFs not only act as strong mitogens but also regulate release of alpha 1-antichymotrypsin, IGF-II/M6P-soluble receptor, and cathepsin D; three proteins that potentially regulate cell proliferation and/or invasion. PMID:7649082

  20. A bi-functional antibody-receptor domain fusion protein simultaneously targeting IGF-IR and VEGF for degradation.

    PubMed

    Shen, Yang; Zeng, Lin; Novosyadlyy, Ruslan; Forest, Amelie; Zhu, Aiping; Korytko, Andrew; Zhang, Haifan; Eastman, Scott W; Topper, Michael; Hindi, Sagit; Covino, Nicole; Persaud, Kris; Kang, Yun; Burtrum, Douglas; Surguladze, David; Prewett, Marie; Chintharlapalli, Sudhakar; Wroblewski, Victor J; Shen, Juqun; Balderes, Paul; Zhu, Zhenping; Snavely, Marshall; Ludwig, Dale L

    2015-01-01

    Bi-specific antibodies (BsAbs), which can simultaneously block 2 tumor targets, have emerged as promising therapeutic alternatives to combinations of individual monoclonal antibodies. Here, we describe the engineering and development of a novel, human bi-functional antibody-receptor domain fusion molecule with ligand capture (bi-AbCap) through the fusion of the domain 2 of human vascular endothelial growth factor receptor 1 (VEGFR1) to an antibody directed against insulin-like growth factor - type I receptor (IGF-IR). The bi-AbCap possesses excellent stability and developability, and is the result of minimal engineering. Beyond potent neutralizing activities against IGF-IR and VEGF, the bi-AbCap is capable of cross-linking VEGF to IGF-IR, leading to co-internalization and degradation of both targets by tumor cells. In multiple mouse xenograft tumor models, the bi-AbCap improves anti-tumor activity over individual monotherapies. More importantly, it exhibits superior inhibition of tumor growth, compared with the combination of anti-IGF-IR and anti-VEGF therapies, via powerful blockade of both direct tumor cell growth and tumor angiogenesis. The unique "capture-for-degradation" mechanism of the bi-AbCap is informative for the design of next-generation bi-functional anti-cancer therapies directed against independent signaling pathways. The bi-AbCap design represents an alternative approach to the creation of dual-targeting antibody fusion molecules by taking advantage of natural receptor-ligand interactions. PMID:26073904

  1. The expressions of IGF-1, BMP-2 and TGF-β1 in cartilage of condylar hyperplasia.

    PubMed

    Meng, Q; Long, X; Deng, M; Cai, H; Li, J

    2011-01-01

    Condylar hyperplasia is a complex post-natal growth abnormality of the mandible and condyle, which leads to facial asymmetry. We investigated the distributions of insulin-like growth factors (IGF-1), bone morphogenetic protein-2 (BMP-2) and transforming growth factor-β1 (TGF-β1) in cartilage of condylar hyperplasia and revealed relationships between age and the cartilaginous thickness. Twenty patients with condylar hyperplasia were divided into four histopathological types. The cartilaginous thickness and age in different histological types were analysed, and the localizations of IGF-1, BMP-2 and TGF-β1 were detected by immunohistochemistry analysis. The cartilaginous thickness of condylar hyperplasia significantly increased. The cartilaginous thickness of type III was significantly thicker than type I and type II, Bivariate correlation revealed a significant correlations between age and the cartilaginous thickness (r = 0·68, P = 0·01). However, the expressions of IGF-1, BMP-2 and TGF-β1 were the strongest in type I. In almost all types of condylar hyperplasia, the presence of IGF-1 and BMP-2 was found mainly in the proliferative chondrocyte layer and the hypertrophic chondrocyte layer, and only a few in the calcified chondrocyte layer. The presence of TGF-β1 widely distributed from the fibrous articular surface to the calcified cartilage. These findings suggest that the proliferative activity of cartilage in condylar hyperplasia is strongly associated with age and cartilaginous thickness. Therefore, the four pathological types of condylar hyperplasia seem more likely to be four discontinuous stages. PMID:20626571

  2. A bi-functional antibody-receptor domain fusion protein simultaneously targeting IGF-IR and VEGF for degradation

    PubMed Central

    Shen, Yang; Zeng, Lin; Novosyadlyy, Ruslan; Forest, Amelie; Zhu, Aiping; Korytko, Andrew; Zhang, Haifan; Eastman, Scott W; Topper, Michael; Hindi, Sagit; Covino, Nicole; Persaud, Kris; Kang, Yun; Burtrum, Douglas; Surguladze, David; Prewett, Marie; Chintharlapalli, Sudhakar; Wroblewski, Victor J; Shen, Juqun; Balderes, Paul; Zhu, Zhenping; Snavely, Marshall; Ludwig, Dale L

    2015-01-01

    Bi-specific antibodies (BsAbs), which can simultaneously block 2 tumor targets, have emerged as promising therapeutic alternatives to combinations of individual monoclonal antibodies. Here, we describe the engineering and development of a novel, human bi-functional antibody-receptor domain fusion molecule with ligand capture (bi-AbCap) through the fusion of the domain 2 of human vascular endothelial growth factor receptor 1 (VEGFR1) to an antibody directed against insulin-like growth factor – type I receptor (IGF-IR). The bi-AbCap possesses excellent stability and developability, and is the result of minimal engineering. Beyond potent neutralizing activities against IGF-IR and VEGF, the bi-AbCap is capable of cross-linking VEGF to IGF-IR, leading to co-internalization and degradation of both targets by tumor cells. In multiple mouse xenograft tumor models, the bi-AbCap improves anti-tumor activity over individual monotherapies. More importantly, it exhibits superior inhibition of tumor growth, compared with the combination of anti-IGF-IR and anti-VEGF therapies, via powerful blockade of both direct tumor cell growth and tumor angiogenesis. The unique “capture-for-degradation” mechanism of the bi-AbCap is informative for the design of next-generation bi-functional anti-cancer therapies directed against independent signaling pathways. The bi-AbCap design represents an alternative approach to the creation of dual-targeting antibody fusion molecules by taking advantage of natural receptor-ligand interactions. PMID:26073904

  3. Fibronectin glycation increases IGF-I induced proliferation of human aortic smooth muscle cells

    PubMed Central

    2012-01-01

    The advanced glycation end products, namely AGEs, contribute to long-termed complications of diabetes mellitus, including macroangiopathy, where smooth muscle cells (SMC) proliferation stimulated by platelet-derived growth factor (PDGF) isoforms and insulin-like growth factor-I (IGF-I) plays an important role. The objective of the present study was to investigate the effect of an AGE-modified extracellular matrix protein on IGF-I induced SMC proliferation and on the IGF-I-IGF binding protein 4 (IGFBP-4) axis under basal conditions and after stimulation with PDGF-BB. IGF-I resulted in significantly higher thymidine incorporation in SMC seeded on AGE-modified fibronectin (AGE-FN) in comparison to cells seeded on fibronectin (FN). This augmented proliferation could not be accounted for by increased expression of IGF-IR, by decreased secretion of IGFBP-4, a binding protein that inhibits IGF-I mitogenic effects or by increased IGF-IR autophosphorylation. PDGF-BB did not modulate IGF-IR and IGFBP-4 mRNA expression in any of the substrata, however, this growth factor elicited opposite effects on the IGFBP-4 content in the conditioned media, increasing it in cells plated on FN and diminishing it in cells plated on AGE-FN. These findings suggest that one mechanism by which AGE-modified proteins is involved in the pathogenesis of diabetes-associated atherosclerosis might be by increasing SMC susceptibility to IGF-I mitogenic effects. PMID:22553932

  4. Promoter-specific expression and imprint status of marsupial IGF2.

    PubMed

    Stringer, Jessica M; Suzuki, Shunsuke; Pask, Andrew J; Shaw, Geoff; Renfree, Marilyn B

    2012-01-01

    In mice and humans, IGF2 has multiple promoters to maintain its complex tissue- and developmental stage-specific imprinting and expression. IGF2 is also imprinted in marsupials, but little is known about its promoter region. In this study, three IGF2 transcripts were isolated from placental and liver samples of the tammar wallaby, Macropus eugenii. Each transcript contained a unique 5' untranslated region, orthologous to the non-coding exons derived from promoters P1-P3 in the human and mouse IGF2 locus. The expression of tammar IGF2 was predominantly from the P2 promoter, similar to humans. Expression of IGF2 was higher in pouch young than in the adult and imprinting was highly tissue and developmental-stage specific. Interestingly, while IGF2 was expressed throughout the placenta, imprinting seemed to be restricted to the vascular, trilaminar region. In addition, IGF2 was monoallelically expressed in the adult mammary gland while in the liver it switched from monoalleleic expression in the pouch young to biallelic in the adult. These data suggest a complex mode of IGF2 regulation in marsupials as seen in eutherian mammals. The conservation of the IGF2 promoters suggests they originated before the divergence of marsupials and eutherians, and have been selectively maintained for at least 160 million years. PMID:22848567

  5. The future is 'ambient'

    NASA Astrophysics Data System (ADS)

    Lugmayr, Artur

    2006-02-01

    The research field of ambient media starts to spread rapidly and first applications for consumer homes are on the way. Ambient media is the logical continuation of research around media. Media has been evolving from old media (e.g. print media), to integrated presentation in one form (multimedia - or new media), to generating a synthetic world (virtual reality), to the natural environment is the user-interface (ambient media), and will be evolving towards real/synthetic undistinguishable media (bio-media or bio-multimedia). After the IT bubble was bursting, multimedia was lacking a vision of potential future scenarios and applications. Within this research paper the potentials, applications, and market available solutions of mobile ambient multimedia are studied. The different features of ambient mobile multimedia are manifold and include wearable computers, adaptive software, context awareness, ubiquitous computers, middleware, and wireless networks. The paper especially focuses on algorithms and methods that can be utilized to realize modern mobile ambient systems.

  6. Epigenetic changes encompassing the IGF2/H19 locus associated with relaxation of IGF2 imprinting and silencing of H19 in Wilms tumor.

    PubMed Central

    Taniguchi, T; Sullivan, M J; Ogawa, O; Reeve, A E

    1995-01-01

    In most tissues IGF2 is expressed from the paternal allele while H19 is expressed from the maternal allele. We have previously shown that in some Wilms tumors the maternal IGF2 imprint is relaxed such that the gene is expressed biallelically. We have now investigated this subset of tumors further and found that biallelic expression of IGF2 was associated with undetectable or very low levels of H19 expression. The relaxation of IGF2 imprinting in Wilms tumors also involved a concomitant reversal in the patterns of DNA methylation of the maternally inherited IGF2 and H19 alleles. Furthermore, the only specific methylation changes that occurred in tumors with relaxation of IGF2 imprinting were solely restricted to the maternal IGF2 and H19 alleles. These data suggest that there has been an acquisition of a paternal epigenotype in these tumors as the result of a pathologic disruption in the normal imprinting of the IGF2 and H19 genes. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:7534414

  7. EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I

    PubMed Central

    Takaoka, Munenori; Smith, Caitlin E.; Mashiba, Michael K.; Okawa, Takaomi; Andl, Claudia D.; El-Deiry, Wafik S.; Nakagawa, Hiroshi

    2010-01-01

    IGF and EGF regulate various physiological and pathological processes. IGF binding protein (IGFBP)-3 regulates cell proliferation in IGF-dependent and -independent fashions. Recently, we identified IGFBP-3 as a novel EGF receptor (EGFR) downstream target molecule in primary and immortalized human esophageal epithelial cells, suggesting an interplay between the EGF and IGF signaling pathways. However, the regulatory mechanisms for IGFBP-3 expression and its functional role in esophageal cell proliferation remain to be elucidated. Herein, we report that IGFBP-3 mRNA and protein were induced upon growth factor deprivation in primary and immortalized human esophageal cells through mechanisms requiring p53-independent de novo mRNA transcription and protein synthesis. This occurred in the face of the activated phosphatidylinositol 3-OH-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. Secreted IGFBP-3 neutralized IGFs and prevented IGF-I receptor (IGF-IR) activation. In contrast, EGF suppressed IGFBP-3 mRNA and protein expression through activation of MAPK in an EGFR-tyrosine kinase-dependent manner to restore the cellular response to IGF-I. When stably overexpressed, wild-type IGFBP-3 but not I56G/L80G/L81G (GGG) mutant IGFBP-3, which has a reduced affinity to IGFs, prevented IGF-I from activating IGF-IR and Akt as well as stimulating cell proliferation. However, unlike other cell types where IGFBP-3 exerts antiproliferative effects, neither wild-type nor GGG mutant IGFBP-3 alone affected cell proliferation or EGFR activity. These results indicate that IGF signaling is subject to negative regulation through IGFBP-3 and positive regulation by EGF, the latter of which suppresses IGFBP-3. This provides a platform for understanding the novel cross talk between EGF- and IGF-mediated pathways. PMID:16210470

  8. Production of recombinant porcine IGF-binding protein-5 and its effect on proliferation of porcine embryonic myoblast cultures in the presence and absence of IGF-I and Long-R3-IGF-I.

    PubMed

    Pampusch, M S; Xi, G; Kamanga-Sollo, E; Loseth, K J; Hathaway, M R; Dayton, W R; White, M E

    2005-04-01

    IGF-binding protein-5 (IGFBP-5) is produced by porcine embryonic myogenic cell (PEMC) cultures and is secreted into the medium. IGFBP-5 may play some role in myogenesis and/or in changes in myogenic cell proliferation that accompany differentiation. IGFBP-5 reportedly may either suppress or stimulate proliferation or differentiation of cultured cells depending on cell type and culture conditions. Additionally, IGFBP-5 has been shown to possess both IGF-dependent and IGF-independent actions in some cell types. The goal of this study was to produce recombinant porcine IGFBP-5 (rpIGFBP-5) and assess its IGF-I-dependent and IGF-I-independent actions on the proliferation of PEMCs. To accomplish this, we have expressed porcine IGFBP-5 in the baculovirus system, purified and characterized the expressed rpIGFBP-5 and produced an anti-porcine IGFBP-5 antibody that neutralizes the biological activity of porcine IGFBP-5. rpIGFBP-5, purified to 98% homogeneity using nickel affinity chromatography and IGF-I affinity chromatography, suppressed IGF-I-stimulated proliferation of PEMCs in a concentration-dependent manner (P>0.05). rpIGFBP-5 also suppressed Long-R3-IGF-I-stimulated proliferation of PEMCs (P>0.05), even in the presence of significant molar excess of Long-R3-IGF-I compared with rpIGFBP-5, demonstrating the IGF-independent activity that rpIGFBP-5 possesses in PEMCs, since Long-R3-IGF-I is an IGF analog that has very low affinity for the IGFBPs but retains its ability to bind to the type I IGF receptor and thereby can stimulate proliferation. The anti-rpIGFBP-5 IgY produced against rpIGFBP-5 specifically recognized native porcine IGFBP-5 in PEMC media that also contained porcine IGFBP-2, -3, and -4. This antibody is capable of neutralizing the effects of both rpIGFBP-5 and endogenously produced porcine IGFBP-5 on PEMCs as well as detecting IGFBP-5 in Western blots. The production of rpIGFBP-5 and a neutralizing antibody to porcine IGFBP-5 provides a powerful tool to

  9. Extracellular signal-regulated kinase and phosphoinositol-3 kinase mediate IGF-1 induced proliferation of fetal sheep cardiomyocytes.

    PubMed

    Sundgren, Nathan C; Giraud, George D; Schultz, Jess M; Lasarev, Michael R; Stork, Philip J S; Thornburg, Kent L

    2003-12-01

    Growth of the fetal heart involves cardiomyocyte enlargement, division, and maturation. Insulin-like growth factor-1 (IGF-1) is implicated in many aspects of growth and is likely to be important in developmental heart growth. IGF-1 stimulates the IGF-1 receptor (IGF1R) and downstream signaling pathways, including extracellular signal-regulated kinase (ERK) and phosphoinositol-3 kinase (PI3K). We hypothesized that IGF-1 stimulates cardiomyocyte proliferation and enlargement through stimulation of the ERK cascade and stimulates cardiomyocyte differentiation through the PI3K cascade. In vivo administration of Long R3 IGF-1 (LR3 IGF-1) did not stimulate cardiomyocyte hypertrophy but led to a decreased percentage of cells that were binucleated in vivo. In culture, LR3 IGF-1 increased myocyte bromodeoxyuridine (BrdU) uptake by three- to five-fold. The blockade of either ERK or PI3K signaling (by UO-126 or LY-294002, respectively) completely abolished BrdU uptake stimulated by LR3 IGF-1. LR3 IGF-1 did not increase footprint area, but as expected, phenylephrine stimulated an increase in binucleated cardiomyocyte size. We conclude that 1) IGF-1 through IGF1R stimulates cardiomyocyte division in vivo; hyperplastic growth is the most likely explanation of IGF-1 stimulated heart growth in vivo; 2) IGF-1 through IGF1R does not stimulate binucleation in vitro or in vivo; 3) IGF-1 through IGF1R does not stimulate hypertrophy either in vivo or in vitro; and 4) IGF-1 through IGF1R requires both ERK and PI3K signaling for proliferation of near-term fetal sheep cardiomyocytes in vitro. PMID:12947030

  10. Endogenous insulin-like growth factor (IGF) binding proteins cause IGF-1 resistance in cultured fibroblasts from a patient with short stature.

    PubMed Central

    Tollefsen, S E; Heath-Monnig, E; Cascieri, M A; Bayne, M L; Daughaday, W H

    1991-01-01

    The ED50 of insulin-like growth factor (IGF)-I-stimulated alpha-aminoisobutyric acid (AIB) uptake (mean +/- SD) in cultured fibroblasts from a child with short stature that we have reported (1.40 +/- 0.24 nM), is significantly higher than the ED50 of IGF-I-stimulated AIB uptake in fibroblasts from 11 normal subjects (0.42 +/- 0.12 nM) and from 127 short children (0.35 +/- 0.11 nM). Similarly, the ED50 of IGF-I-stimulated thymidine incorporation in fibroblasts from this child is 2.8 times higher than that in fibroblasts from four normal subjects. To minimize potential modulation of IGF-I action by endogenous IGF binding proteins in these assays, fibroblast responsiveness to [Q3,A4,Y15,L16]IGF-I, an IGF-I variant that has a 600-fold reduced affinity for serum IGF binding proteins, has been examined. The biological activity of this variant is comparable in the patient's and normal fibroblasts, suggesting that the resistance to IGF-I action cannot be attributed to a defective IGF-I receptor. To investigate directly the possibility that IGF-I sensitivity in the patient's fibroblasts is reduced by endogenous IGF binding proteins (IGFBP), binding proteins that are secreted into AIB assay buffer during a 3-h collection and that are cell-associated at the end of the collection have been analyzed. Ligand blot analysis of conditioned AIB assay buffer demonstrates that fibroblasts from the patient secrete 1.3-2.2 times more of Mr 46,400/42,900, 32,000, and 26,800 binding proteins than normal fibroblasts. The major difference between fibroblasts from the patient and from normal subjects is a striking 10-fold increase in the amount of a cell surface Mr 32,000 binding protein in the patient's fibroblasts. The Mr 32,000 binding protein is similar in size to IGFB-1 and different from IGFBP-2 and IGFBP-3, but it does not cross-react with an antibody against IGFBP-1. We conclude that the resistance to IGF-I action in the patient's fibroblasts is caused by an abnormal production and

  11. Effects of human insulin and insulin aspart preparations on levels of IGF-I, IGFBPs and IGF bioactivity in patients with type 1 diabetes

    PubMed Central

    2014-01-01

    Background Insulin aspart (IAsp) and its biphasic preparations BIAsp50 and BIAsp70 (containing 50% and 70% IAsp, respectively) have distinct glucose-lowering properties as compared to human insulin (HI). We investigated whether this affected the circulating IGF-system which depends on the hepatic insulin exposure. Methods In a randomized, four-period crossover study, 19 patients with type 1 diabetes received identical doses (0.2 U/kg sc) of IAsp, BIAsp70, BIAsp50 and HI together with a standardized meal. Serum total IGF-I and IGFBP-1 to -3 were measured by immunoassays for nine hours post-prandially. Bioactive IGF was determined by an in-house, cell-based IGF-I receptor kinase activation (KIRA) assay. Results Despite marked differences in peripheral insulin concentrations and plasma glucose, the four insulin preparations resulted in parallel decreases in IGFBP-1 levels during the first 3 hours, and parallel increases during the last part of the study (3–9 hours). Thus, only minor significances were seen. Insulin aspart and human insulin resulted in a lower area under the curve (AUC) during the first 3 hours as compared to BIAsp70 (p = 0.009), and overall, human insulin resulted in a lower IGFBP-1 AUC than BIAsp70 (p = 0.025). Nevertheless, responses and AUCs of bioactive IGF were similar for all four insulin preparations. Changes in levels of bioactive IGF were inversely correlated to those of IGFBP-1, increasing during the first 3 hours, whereafter levels declined (-0.83 ≤ r ≤ -0.30; all p-values <0.05). Total IGF-I and IGFBP-3 remained stable during the 9 hours, whereas IGFBP-2 changed opposite of IGFBP-1, increasing after 3–4 hours whereafter levels gradually declined. The four insulin preparations resulted in similar profiles and AUCs of total IGF-I, IGFBP-2 and IGFBP-3. Conclusions Despite distinct glucose-lowering properties, the tested insulin preparations had similar effects on IGF-I concentration and IGF bioactivity, IGFBP-2

  12. Integrating metabolism and longevity through insulin and IGF1 signaling

    PubMed Central

    Sadagurski, Marianna; White, Morris F.

    2014-01-01

    Understanding how metabolism integrates nutrient homeostasis with life span is a complicated undertaking. The insulin pathway coordinates growth, development, metabolic homoeostasis, fertility and stress resistance, which ultimately influence lifespan. From a clinical perspective, compensatory hyperinsulinemia to overcome systemic insulin resistance is thought to be a healthy goal, because it circumvents to immediate catastrophic consequences of hyperglycemia; however, work in flies, nematodes and mice indicate that excess insulin signaling ultimately damages cellular function and accelerates aging. Maintenance of the central nervous system (CNS) has particular importance for lifespan. Depending upon the exact site, reduced insulin/IGF1 signaling in the CNS can dysregulate peripheral energy homeostasis and metabolism, promote obesity, and extend lifespan. In this review, we explore how genetic manipulations of insulin/IGF1 signaling components are beginning to reveal neuronal circuits which might resolve the central regulation of systemic metabolism from organism longevity. PMID:23391244

  13. GH/IGF-I Transgene Expression on Muscle Homeostasis

    NASA Technical Reports Server (NTRS)

    Schwartz, Robert J.

    1999-01-01

    We propose to test the hypothesis that the growth hormone/ insulin like growth factor-I axis through autocrine/paracrine mechanisms may provide long term muscle homeostasis under conditions of prolonged weightlessness. As a key alternative to hormone replacement therapy, ectopic production of hGH, growth hormone releasing hormone (GHRH), and IGF-I will be studied for its potential on muscle mass impact in transgenic mice under simulated microgravity. Expression of either hGH or IGF-I would provide a chronic source of a growth-promoting protein whose biosynthesis or secretion is shut down in space. Muscle expression of the IGF-I transgene has demonstrated about a 20% increase in hind limb muscle mass over control nontransgenic litter mates. These recent experiments, also establish the utility of hind-limb suspension in mice as a workable model to study atrophy in weight bearing muscles. Thus, transgenic mice will be used in hind-limb suspension models to determine the role of GH/IGF-I on maintenance of muscle mass and whether concentric exercises might act in synergy with hormone treatment. As a means to engineer and ensure long-term protein production that would be workable in humans, gene therapy technology will be used by to monitor muscle mass preservation during hind-limb suspension, after direct intramuscular injection of a genetically engineered muscle-specific vector expressing GHRH. Effects of this gene-based therapy will be assessed in both fast twitch (medial gastrocnemius) and slow twitch muscle (soleus). End-points include muscle size, ultrastructure, fiber type, and contractile function, in normal animals, hind limb suspension, and reambutation.

  14. Regulation of insulin-like growth factor-I (IGF-I) and IGF-binding proteins by tumor necrosis factor.

    PubMed

    Fan, J; Char, D; Bagby, G J; Gelato, M C; Lang, C H

    1995-11-01

    The purpose of the present study was to determine 1) whether exogenous administration of tumor necrosis factor-alpha (TNF-alpha) alters insulin-like growth factor-I (IGF-I) and IGF-binding proteins (BPs) and 2) whether the enhanced endogenous production of TNF mediates the lipopolysaccharide (LPS)-induced changes in the IGF system. The overnight infusion of murine TNF-alpha reduced circulating concentrations of both growth hormone (GH) and IGF-I in fasted rats. Furthermore, TNF-alpha decreased IGF-I content in liver, gastrocnemius muscle, and pituitary. In contrast, TNF-alpha increased IGF-I content in kidney and brain. IGFBP-1 was increased in plasma, liver, and muscle in response to TNF-alpha. In a second study, rats were injected with LPS after treatment with a neutralizing anti-TNF antibody (Ab), and blood and tissues were collected 4 h later. In LPS-treated rats, plasma concentrations of GH and IGF-I were reduced. LPS also decreased the IGF-I content in liver and skeletal muscle and increased plasma, liver, and muscle concentrations of IGFBP-1. Pretreatment with anti-TNF Ab attenuated the LPS-induced reduction in IGF-I and the increased IGFBP-1 in plasma and liver and completely prevented the decrease in IGF-I observed in muscle. In contrast, the LPS-induced decrease in plasma GH and the increased IGFBP-1 observed in muscle were unaltered by the anti-TNF Ab.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7503312

  15. Effect of recombinant porcine IGF-binding protein-3 on proliferation of embryonic porcine myogenic cell cultures in the presence and absence of IGF-I.

    PubMed

    Pampusch, M S; Kamanga-Sollo, E; White, M E; Hathaway, M R; Dayton, W R

    2003-02-01

    IGF-binding protein (IGFBP)-3 is produced by cultured porcine embryonic myogenic cell (PEMC) cultures and is secreted into the medium. Levels of secreted IGFBP-3 and IGFBP-3 mRNA are significantly reduced during differentiation and increase after differentiation is complete, suggesting that IGFBP-3 may play some role in myogenesis and/or in changes in myogenic cell proliferation that accompany differentiation. IGFBP-3 reportedly may either suppress or stimulate proliferation of cultured cells depending on cell type. Additionally, IGFBP-3 has been shown to affect proliferation via both IGF-dependent and IGF-independent mechanisms in some cell types but not all. Currently, the effect, if any, of IGFBP-3 on myogenic cell proliferation is not known. Consequently, the goal of this study was to assess the IGF-I-dependent and IGF-I-independent actions of recombinant porcine IGFBP-3 on proliferation of cultured porcine myogenic cells. To facilitate these investigations, we have expressed porcine IGFBP-3 in the baculovirus system, purified and characterized the expressed recombinant porcine IGFBP-3 (rpIGFBP-3), and produced and characterized an anti-porcine IGFBP-3 antibody that neutralizes the biological activity of porcine IGFBP-3. rpIGFBP-3 suppressed IGF-I-stimulated proliferation of PEMCs in a concentration-dependent manner with equimolar concentrations of IGF-I and rpIGFBP-3, resulting in complete suppression of IGF-I-stimulated proliferation. rpIGFBP-3 also suppressed Long-R3-IGF-I-stimulated proliferation of PEMC, indicating that rpIGFBP-3 possesses IGF-independent activity in this cell system. These data have established that IGFBP-3 has the potential to affect proliferation of PEMCs during critical periods of muscle development that may impact ultimate muscle mass achievable postnatally. PMID:12553871

  16. Structural lubricity under ambient conditions

    PubMed Central

    Cihan, Ebru; İpek, Semran; Durgun, Engin; Baykara, Mehmet Z.

    2016-01-01

    Despite its fundamental importance, physical mechanisms that govern friction are poorly understood. While a state of ultra-low friction, termed structural lubricity, is expected for any clean, atomically flat interface consisting of two different materials with incommensurate structures, some associated predictions could only be quantitatively confirmed under ultra-high vacuum (UHV) conditions so far. Here, we report structurally lubric sliding under ambient conditions at mesoscopic (∼4,000–130,000 nm2) interfaces formed by gold islands on graphite. Ab initio calculations reveal that the gold–graphite interface is expected to remain largely free from contaminant molecules, leading to structurally lubric sliding. The experiments reported here demonstrate the potential for practical lubrication schemes for micro- and nano-electromechanical systems, which would mainly rely on an atomic-scale structural mismatch between the slider and substrate components, via the utilization of material systems featuring clean, atomically flat interfaces under ambient conditions. PMID:27350035

  17. Distinct organ-specific up- and down-regulation of IGF-I and IGF-II mRNA in various organs of a GH-overexpressing transgenic Nile tilapia.

    PubMed

    Eppler, Elisabeth; Berishvili, Giorgi; Mazel, Peter; Caelers, Antje; Hwang, Gyulin; Maclean, Norman; Reinecke, Manfred

    2010-04-01

    Several lines of GH-overexpressing fish have been produced and characterized concerning organ integrity, growth, fertility and health but few and contradictory data are available on IGF-I that mediates most effects of GH. Furthermore, nothing is known on IGF-II. Thus, the expression of both IGFs in liver and various extrahepatic sites of adult transgenic (GH-overexpressing) tilapia and age-matched wild-type fish was determined by real-time PCR. Both IGF-I and IGF-II mRNA were found in all organs investigated and were increased in gills, kidney, intestine, heart, testes, skeletal muscle and brain of the transgenics (IGF-I: 1.4-4-fold; IGF-II: 1.7-4.2-fold). Except for liver, brain and testis the increase in IGF-I mRNA was higher than that in IGF-II mRNA. In pituitary, no significant change in IGF-I or IGF-II mRNA was detected. In spleen, however, IGF-I and IGF-II mRNA were both decreased in the transgenics, IGF-I mRNA even by the 19-fold. In agreement, in situ hybridisation revealed a largely reduced number of IGF-I mRNA-containing leukocytes and macrophages when compared to wild-type. These observations may contribute to better understanding the reported impaired health of GH-transgenic fish. Growth enhancement of the transgenics may be due to the increased expression of both IGF-I and IGF-II in extrahepatic sites. It is also reasonable that the markedly enhanced expression of liver IGF-II mRNA that may mimick an early developmental stage is a further reason for increased growth. PMID:19669925

  18. Organ-specific expression of IGF-I during early development of bony fish as revealed in the tilapia, Oreochromis niloticus, by in situ hybridization and immunohistochemistry: indication for the particular importance of local IGF-I.

    PubMed

    Berishvili, Giorgi; Shved, Natallia; Eppler, Elisabeth; Clota, Frederic; Baroiller, Jean-François; Reinecke, Manfred

    2006-08-01

    The cellular sites of insulin-like growth factor I (IGF-I) synthesis in the early developing tilapia (0-140 days post fertilization, DPF) were investigated. IGF-I mRNA and peptide appeared in liver as early as 4 DPF and in gastro-intestinal epithelial cells between 5-9 DPF. In exocrine pancreas, the expression of IGF-I started at 4 DPF and continued until 90 DPF. IGF-I production was detected in islets at 6 DPF in non-insulin cells and occurred throughout life. In renal tubules and ducts, IGF-I production started at 8 DPF. IGF-I production in chondrocytes had its onset at 4 DPF, was more pronounced in growing regions and was also found in adults. IGF-I mRNA and peptide appeared in the cytoplasm of skeletal muscle cells at 4 DPF. In gill chloride cells, IGF-I production started at 6 DPF. At 13 DPF, IGF-I was detected in cardiac myocytes. IGF-I-producing epidermal cells appeared at 5 DPF. In brain and ganglia, IGF-I was expressed in virtually all neurones from 6 to 29 DPF, their number decreasing with age. Neurosecretory IGF-I-immunoreactive axons were first seen in the neurohypophysis around 17 DPF. Endocrine cells of the adenohypophysis exhibited IGF-I mRNA at 28 DPF and IGF-I immunoreactivity at 40 DPF. Thus, IGF-I appeared early (4-5 DPF), first in liver, the main source of endocrine IGF-I, and then in organs involved in growth or metabolism. The expression of IGF-I was more pronounced during development than in juvenile and adult life. Local IGF-I therefore seems to have a high functional impact in early growth, metabolism and organogenesis. PMID:16596395

  19. AMBIENT AIR MONITORING STRATEGY

    EPA Science Inventory

    The Clean Air Act requires EPA to establish national ambient air quality standards and to regulate as necessary, hazardous air pollutants. EPA uses ambient air monitoring to determine current air quality conditions, and to assess progress toward meeting these standards and relat...

  20. Ambient Tropospheric Particles

    EPA Science Inventory

    Atmospheric particulate matter (PM) is a complex mixture of solid and liquid particles suspended in ambient air (also known as the atmospheric aerosol). Ambient PM arises from a wide-range of sources and/or processes, and consists of particles of different shapes, sizes, and com...

  1. MIR retroposon exonization promotes evolutionary variability and generates species-specific expression of IGF-1 splice variants.

    PubMed

    Annibalini, Giosuè; Bielli, Pamela; De Santi, Mauro; Agostini, Deborah; Guescini, Michele; Sisti, Davide; Contarelli, Serena; Brandi, Giorgio; Villarini, Anna; Stocchi, Vilberto; Sette, Claudio; Barbieri, Elena

    2016-05-01

    Insulin-like growth factor (IGF) -1 is a pleiotropic hormone exerting mitogenic and anti-apoptotic effects. Inclusion or exclusion of exon 5 into the IGF-1 mRNA gives rise to three transcripts, IGF-1Ea, IGF-1Eb and IGF-1Ec, which yield three different C-terminal extensions called Ea, Eb and Ec peptides. The biological significance of the IGF-1 splice variants and how the E-peptides affect the actions of mature IGF-1 are largely unknown. In this study we investigated the origin and conservation of the IGF-1 E-peptides and we compared the pattern of expression of the IGF-1 isoforms in vivo, in nine mammalian species, and in vitro using human and mouse IGF-1 minigenes. Our analysis showed that only IGF-1Ea is conserved among all vertebrates, whereas IGF-1Eb and IGF-1Ec are an evolutionary novelty originated from the exonization of a mammalian interspersed repetitive-b (MIR-b) element. Both IGF-1Eb and IGF-1Ec mRNAs were constitutively expressed in all mammalian species analyzed but their expression ratio varies greatly among species. Using IGF-1 minigenes we demonstrated that divergence in cis-acting regulatory elements between human and mouse conferred species-specific features to the exon 5 region. Finally, the protein-coding sequences of exon 5 showed low rate of synonymous mutations and contain disorder-promoting amino acids, suggesting a regulatory role for these domains. In conclusion, exonization of a MIR-b element in the IGF-1 gene determined gain of exon 5 during mammalian evolution. Alternative splicing of this novel exon added new regulatory elements at the mRNA and protein level potentially able to regulate the mature IGF-1 across tissues and species. PMID:27048986

  2. The impact of a human IGF-II analog ([Leu27]IGF-II) on fetal growth in a mouse model of fetal growth restriction.

    PubMed

    Charnock, Jayne C; Dilworth, Mark R; Aplin, John D; Sibley, Colin P; Westwood, Melissa; Crocker, Ian P

    2016-01-01

    Enhancing placental insulin-like growth factor (IGF) availability appears to be an attractive strategy for improving outcomes in fetal growth restriction (FGR). Our approach was the novel use of [Leu(27)]IGF-II, a human IGF-II analog that binds the IGF-II clearance receptor IGF-IIR in fetal growth-restricted (FGR) mice. We hypothesized that the impact of [Leu(27)]IGF-II infusion in C57BL/6J (wild-type) and endothelial nitric oxide synthase knockout (eNOS(-/-); FGR) mice would be to enhance fetal growth and investigated this from mid- to late gestation; 1 mg·kg(-1)·day(-1) [Leu(27)]IGF-II was delivered via a subcutaneous miniosmotic pump from E12.5 to E18.5. Fetal and placental weights recorded at E18.5 were used to generate frequency distribution curves; fetuses <5th centile were deemed growth restricted. Placentas were harvested for immunohistochemical analysis of the IGF system, and maternal serum was collected for measurement of exogenously administered IGF-II. In WT pregnancies, [Leu(27)]IGF-II treatment halved the number of FGR fetuses, reduced fetal(P = 0.028) and placental weight variations (P = 0.0032), and increased the numbers of pups close to the mean fetal weight (131 vs. 112 pups within 1 SD). Mixed-model analysis confirmed litter size to be negatively correlated with fetal and placental weight and showed that [Leu(27)]IGF-II preferentially improved fetal weight in the largest litters, as defined by number. Unidirectional (14C)MeAIB transfer per gram placenta (System A amino acid transporter activity) was inversely correlated with fetal weight in [Leu(27)]IGF-II-treated WT animals (P < 0.01). In eNOS(-/-) mice, [Leu(27)]IGF-II reduced the number of FGR fetuses(1 vs. 5 in the untreated group). The observed reduction in FGR pup numbers in both C57 and eNOS(-/-) litters suggests the use of this analog as a means of standardizing and rescuing fetal growth, preferentially in the smallest offspring. PMID:26530156

  3. The impact of a human IGF-II analog ([Leu27]IGF-II) on fetal growth in a mouse model of fetal growth restriction

    PubMed Central

    Charnock, Jayne C.; Dilworth, Mark R.; Aplin, John D.; Sibley, Colin P.; Westwood, Melissa

    2015-01-01

    Enhancing placental insulin-like growth factor (IGF) availability appears to be an attractive strategy for improving outcomes in fetal growth restriction (FGR). Our approach was the novel use of [Leu27]IGF-II, a human IGF-II analog that binds the IGF-II clearance receptor IGF-IIR in fetal growth-restricted (FGR) mice. We hypothesized that the impact of [Leu27]IGF-II infusion in C57BL/6J (wild-type) and endothelial nitric oxide synthase knockout (eNOS−/−; FGR) mice would be to enhance fetal growth and investigated this from mid- to late gestation; 1 mg·kg−1·day−1 [Leu27]IGF-II was delivered via a subcutaneous miniosmotic pump from E12.5 to E18.5. Fetal and placental weights recorded at E18.5 were used to generate frequency distribution curves; fetuses <5th centile were deemed growth restricted. Placentas were harvested for immunohistochemical analysis of the IGF system, and maternal serum was collected for measurement of exogenously administered IGF-II. In WT pregnancies, [Leu27]IGF-II treatment halved the number of FGR fetuses, reduced fetal(P = 0.028) and placental weight variations (P = 0.0032), and increased the numbers of pups close to the mean fetal weight (131 vs. 112 pups within 1 SD). Mixed-model analysis confirmed litter size to be negatively correlated with fetal and placental weight and showed that [Leu27]IGF-II preferentially improved fetal weight in the largest litters, as defined by number. Unidirectional 14CMeAIB transfer per gram placenta (System A amino acid transporter activity) was inversely correlated with fetal weight in [Leu27]IGF-II-treated WT animals (P < 0.01). In eNOS−/− mice, [Leu27]IGF-II reduced the number of FGR fetuses(1 vs. 5 in the untreated group). The observed reduction in FGR pup numbers in both C57 and eNOS−/− litters suggests the use of this analog as a means of standardizing and rescuing fetal growth, preferentially in the smallest offspring. PMID:26530156

  4. Regulation of insulin-like growth factor (IGF) binding protein-5 in the T47D human breast carcinoma cell line by IGF-I and retinoic acid.

    PubMed

    Shemer, J; Yaron, A; Werner, H; Shao, Z M; Sheikh, M S; Fontana, J A; LeRoith, D; Roberts, C T

    1993-11-01

    The T47D human breast carcinoma cell line has been shown to synthesize insulin-like growth factor-I (IGF-I) binding proteins (IGFBPs) and IGF-I receptors, and to exhibit a mitogenic response to exogenous IGF-I. We have used T47D cells to investigate the regulation of IGFBPs by IGF-I and retinoic acid (RA), agents that affect cell proliferation and have been shown to regulate IGFBP levels in other cell types. Exposure of T47D cells to IGF-I resulted in the appearance of IGFBP-2, -4, and -5 in conditioned medium but had no effect on the levels of IGFBPs in Triton X-100-extracted cells. This effect was most pronounced for IGFBP-5 and was also elicited by an IGF-I analog that retains affinity for IGFBPs but not by insulin or IGF analogs that have decreased affinity for IGFBPs. Additionally, this effect was not associated with a change in IGFBP-5 messenger RNA (mRNA) levels; however, the appearance of IGFBP-5 in the conditioned medium was inhibited by an anti-IGF-I receptor antibody (alpha IR-3). RA decreased IGFBP-5 mRNA levels and cell-associated IGFBP-5 in both the presence and absence of IGF-I and inhibited the IGF-I-stimulated secretion of IGFBP-5 into T47D cell conditioned medium. These results suggest that IGF-I increases IGFBP-5 levels in the T47D cell line both through direct interaction with IGFBP-5 as well as through a receptor-mediated process that does not require direct interaction with IGFBPs. The latter results are consistent with an effect of IGF-I on a factor that may modulate an IGFBP protease activity. The inhibitory effect of RA, on the other hand, appears to be due primarily to regulation of IGFBP-5 mRNA levels. Thus, IGFBP-5 accumulation appears to be positively regulated by IGF-I, potentially at the level of susceptibility to proteolysis, and negatively regulated at the level of gene expression by RA. PMID:7521344

  5. IGF2 DNA methylation is a modulator of newborn’s fetal growth and development

    PubMed Central

    St-Pierre, Julie; Hivert, Marie-France; Perron, Patrice; Poirier, Paul; Guay, Simon-Pierre; Brisson, Diane; Bouchard, Luigi

    2012-01-01

    The insulin-like growth factor 2 (IGF2) gene, located within a cluster of imprinted genes on chromosome 11p15, encodes a fetal and placental growth factor affecting birth weight. DNA methylation variability at the IGF2 gene locus has been previously reported but its consequences on fetal growth and development are still mostly unknown in normal pediatric population. We collected one hundred placenta biopsies from 50 women with corresponding maternal and cord blood samples and measured anthropometric indices, blood pressure and metabolic phenotypes using standardized procedures. IGF2/H19 DNA methylation and IGF2 circulating levels were assessed using sodium bisulfite pyrosequencing and ELISA, respectively. Placental IGF2 (DMR0 and DMR2) DNA methylation levels were correlated with newborn’s fetal growth indices, such as weight, and with maternal IGF2 circulating concentration at the third trimester of pregnancy, whereas H19 (DMR) DNA methylation levels were correlated with IGF2 levels in cord blood. The maternal genotype of a known IGF2/H19 polymorphism (rs2107425) was associated with birth weight. Taken together, we showed that IGF2/H19 epigenotype and genotypes independently account for 31% of the newborn’s weight variance. No association was observed with maternal diabetic status, glucose concentrations or prenatal maternal body mass index. This is the first study showing that DNA methylation at the IGF2/H19 genes locus may act as a modulator of IGF2 newborn’s fetal growth and development within normal range. IGF2/H19 DNA methylation could represent a cornerstone in linking birth weight and fetal metabolic programming of late onset obesity. PMID:22907587

  6. Altered Methylation of IGF2 Locus 20 Years after Preterm Birth at Very Low Birth Weight

    PubMed Central

    Wehkalampi, Karoliina; Muurinen, Mari; Wirta, Sara Bruce; Hannula-Jouppi, Katariina; Hovi, Petteri; Järvenpää, Anna-Liisa; Eriksson, Johan G.; Andersson, Sture; Kere, Juha; Kajantie, Eero

    2013-01-01

    Introduction People born preterm at very low birth weight (VLBW, ≤1500g) have higher rates of risk factors for adult-onset diseases, including cardiovascular diseases and type 2 diabetes. These risks may be mediated through epigenetic modification of genes that are critical to normal growth and development. Methods We measured the methylation level of an imprinted insulin-like-growth-factor 2 (IGF2) locus (IGF2/H19) in young adults born preterm at VLBW and in their peers born at term. We studied 158 VLBW and 161 control subjects aged 18 to 27 years from the Helsinki Study of Very Low Birth Weight Adults. Methylation fraction at two IGF2 differentially methylated regions (DMRs) – IGF2 antisense transcript (IGF2AS, also known as IGF2 DMR0) and last exon of IGF2 (IGF2_05, also known as IGF2 DMR2) – were measured with Sequenom Epityper. We used linear regression and adjustment for covariates to compare methylation fractions at these DMRs between VLBW and control subjects. Results At one IGF2AS CpG site, methylation was significantly lower in VLBW than in control subjects, mean difference −0.017 (95% CI; −0.028, −0.005), P = 0.004. Methylation at IGF2_05 was not different between the groups. Conclusions Methylation of IGF2AS is altered 20 years after preterm birth at VLBW. Altered methylation may be a mechanism of later increased disease risk but more data are needed to indicate causality. PMID:23840686

  7. IGF-I enhances cellular senescence via the reactive oxygen species-p53 pathway

    SciTech Connect

    Handayaningsih, Anastasia-Evi; Takahashi, Michiko; Fukuoka, Hidenori; Iguchi, Genzo; Nishizawa, Hitoshi; Yamamoto, Masaaki; Suda, Kentaro; Takahashi, Yutaka

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Cellular senescence plays an important role in tumorigenesis and aging process. Black-Right-Pointing-Pointer We demonstrated IGF-I enhanced cellular senescence in primary confluent cells. Black-Right-Pointing-Pointer IGF-I enhanced cellular senescence in the ROS and p53-dependent manner. Black-Right-Pointing-Pointer These results may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging. -- Abstract: Cellular senescence is characterized by growth arrest, enlarged and flattened cell morphology, the expression of senescence-associated {beta}-galactosidase (SA-{beta}-gal), and by activation of tumor suppressor networks. Insulin-like growth factor-I (IGF-I) plays a critical role in cellular growth, proliferation, tumorigenesis, and regulation of aging. In the present study, we show that IGF-I enhances cellular senescence in mouse, rat, and human primary cells in the confluent state. IGF-I induced expression of a DNA damage marker, {gamma}H2AX, the increased levels of p53 and p21 proteins, and activated SA-{beta}-gal. In the confluent state, an altered downstream signaling of IGF-I receptor was observed. Treatment with a reactive oxygen species (ROS) scavenger, N-acetylcystein (NAC) significantly suppressed induction of these markers, indicating that ROS are involved in the induction of cellular senescence by IGF-I. In p53-null mouse embryonic fibroblasts, the IGF-I-induced augmentation of SA-{beta}-gal and p21 was inhibited, demonstrating that p53 is required for cellular senescence induced by IGF-I. Thus, these data reveal a novel pathway whereby IGF-I enhances cellular senescence in the ROS and p53-dependent manner and may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging.

  8. Associations between summertime ambient pollutants and respiratory morbidity in New York City: Comparison of results using ambient concentrations versus predicted exposures

    EPA Science Inventory

    Epidemiological analyses of air quality often estimate human exposure from ambient monitoring data, potentially leading to exposure misclassification and subsequent bias in estimated health risks. To investigate this, we conducted a case-crossover study of summertime ambient ozon...

  9. Overexpression of the IGF-II/M6P Receptor in Mouse Fibroblast Cell Lines Differentially Alters Expression Profiles of Genes Involved in Alzheimer’s Disease-Related Pathology

    PubMed Central

    Wang, Yanlin; Thinakaran, Gopal; Kar, Satyabrata

    2014-01-01

    Alzheimer’s disease (AD) is the most common type of senile dementia affecting elderly people. The processing of amyloid precursor protein (APP) leading to the generation of β-amyloid (Aβ) peptide contributes to neurodegeneration and development of AD pathology. The endocytic trafficking pathway, which comprises of the endosomes and lysosomes, acts as an important site for Aβ generation, and endocytic dysfunction has been linked to increased Aβ production and loss of neurons in AD brains. Since insulin-like growth factor-II (IGF-II) receptor plays a critical role in the transport of lysosomal enzymes from the trans-Golgi network to endosomes, it is likely that the receptor may have a role in regulating Aβ metabolism in AD pathology. However, very little is known on how altered levels of the IGF-II receptor can influence the expression/function of various molecules involved in AD pathology. To address this issue, we evaluated the expression profiles of 87 selected genes related to AD pathology in mouse fibroblast MS cells that are deficient in murine IGF-II receptor and corresponding MS9II cells overexpressing ∼500 times the human IGF-II receptors. Our results reveal that an elevation in IGF-II receptor levels alters the expression profiles of a number of genes including APP as well as enzymes regulating Aβ production, degradation and clearance mechanisms. Additionally, it influences the expression of various lysosomal enzymes and protein kinases that are involved in Aβ toxicity. IGF-II receptor overexpression also alters expression of several genes involved in intracellular signalling as well as cholesterol metabolism, which play a critical role in AD pathology. The altered gene profiles observed in this study closely match with the corresponding protein levels, with a few exceptions. These results, taken together, suggest that an elevation in IGF-II receptor levels can influence the expression profiles of transcripts as well as proteins that are involved

  10. IGF-I enhances cellular senescence via the reactive oxygen species-p53 pathway.

    PubMed

    Handayaningsih, Anastasia-Evi; Takahashi, Michiko; Fukuoka, Hidenori; Iguchi, Genzo; Nishizawa, Hitoshi; Yamamoto, Masaaki; Suda, Kentaro; Takahashi, Yutaka

    2012-08-24

    Cellular senescence is characterized by growth arrest, enlarged and flattened cell morphology, the expression of senescence-associated β-galactosidase (SA-β-gal), and by activation of tumor suppressor networks. Insulin-like growth factor-I (IGF-I) plays a critical role in cellular growth, proliferation, tumorigenesis, and regulation of aging. In the present study, we show that IGF-I enhances cellular senescence in mouse, rat, and human primary cells in the confluent state. IGF-I induced expression of a DNA damage marker, γH2AX, the increased levels of p53 and p21 proteins, and activated SA-β-gal. In the confluent state, an altered downstream signaling of IGF-I receptor was observed. Treatment with a reactive oxygen species (ROS) scavenger, N-acetylcystein (NAC) significantly suppressed induction of these markers, indicating that ROS are involved in the induction of cellular senescence by IGF-I. In p53-null mouse embryonic fibroblasts, the IGF-I-induced augmentation of SA-β-gal and p21 was inhibited, demonstrating that p53 is required for cellular senescence induced by IGF-I. Thus, these data reveal a novel pathway whereby IGF-I enhances cellular senescence in the ROS and p53-dependent manner and may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging. PMID:22877754