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Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN

The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that...

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Autores principales: Singh, Karmveer, Maity, Pallab, Krug, Linda, Meyer, Patrick, Treiber, Nicolai, Lucas, Tanja, Basu, Abhijit, Kochanek, Stefan, Wlaschek, Meinhard, Geiger, Hartmut, Scharffetter-Kochanek, Karin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309668/
https://www.ncbi.nlm.nih.gov/pubmed/25520316
http://dx.doi.org/10.15252/emmm.201404082
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author Singh, Karmveer
Maity, Pallab
Krug, Linda
Meyer, Patrick
Treiber, Nicolai
Lucas, Tanja
Basu, Abhijit
Kochanek, Stefan
Wlaschek, Meinhard
Geiger, Hartmut
Scharffetter-Kochanek, Karin
author_facet Singh, Karmveer
Maity, Pallab
Krug, Linda
Meyer, Patrick
Treiber, Nicolai
Lucas, Tanja
Basu, Abhijit
Kochanek, Stefan
Wlaschek, Meinhard
Geiger, Hartmut
Scharffetter-Kochanek, Karin
author_sort Singh, Karmveer
collection PubMed
description The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that IGF-1 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions ([Image: see text]) in mitochondria, either by chemical inhibition of complex I or by genetic silencing of [Image: see text]-dismutating mitochondrial Sod2. The [Image: see text]-dependent suppression of IGF-1 signalling resulted in decreased proliferation of murine dermal fibroblasts, affected translation initiation factors and suppressed the expression of α1(I), α1(III), and α2(I) collagen, the hallmarks of skin ageing. Enhanced [Image: see text] led to activation of the phosphatases PTP1B and PTEN, which via dephosphorylation of the IGF-1 receptor and phosphatidylinositol 3,4,5-triphosphate dampened IGF-1 signalling. Genetic and pharmacologic inhibition of PTP1B and PTEN abrogated [Image: see text]-induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with [Image: see text], PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies.
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spelling pubmed-43096682015-02-04 Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN Singh, Karmveer Maity, Pallab Krug, Linda Meyer, Patrick Treiber, Nicolai Lucas, Tanja Basu, Abhijit Kochanek, Stefan Wlaschek, Meinhard Geiger, Hartmut Scharffetter-Kochanek, Karin EMBO Mol Med Research Articles The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that IGF-1 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions ([Image: see text]) in mitochondria, either by chemical inhibition of complex I or by genetic silencing of [Image: see text]-dismutating mitochondrial Sod2. The [Image: see text]-dependent suppression of IGF-1 signalling resulted in decreased proliferation of murine dermal fibroblasts, affected translation initiation factors and suppressed the expression of α1(I), α1(III), and α2(I) collagen, the hallmarks of skin ageing. Enhanced [Image: see text] led to activation of the phosphatases PTP1B and PTEN, which via dephosphorylation of the IGF-1 receptor and phosphatidylinositol 3,4,5-triphosphate dampened IGF-1 signalling. Genetic and pharmacologic inhibition of PTP1B and PTEN abrogated [Image: see text]-induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with [Image: see text], PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies. BlackWell Publishing Ltd 2015-01 2014-12-17 /pmc/articles/PMC4309668/ /pubmed/25520316 http://dx.doi.org/10.15252/emmm.201404082 Text en © 2014 The Authors. Published under the terms of the CC BY 4.0 license http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Singh, Karmveer
Maity, Pallab
Krug, Linda
Meyer, Patrick
Treiber, Nicolai
Lucas, Tanja
Basu, Abhijit
Kochanek, Stefan
Wlaschek, Meinhard
Geiger, Hartmut
Scharffetter-Kochanek, Karin
Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN
title Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN
title_full Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN
title_fullStr Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN
title_full_unstemmed Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN
title_short Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN
title_sort superoxide anion radicals induce igf-1 resistance through concomitant activation of ptp1b and pten
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309668/
https://www.ncbi.nlm.nih.gov/pubmed/25520316
http://dx.doi.org/10.15252/emmm.201404082
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