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


ABSTRACT: 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 (O2?-) in mitochondria, either by chemical inhibition of complex I or by genetic silencing of O2?--dismutating mitochondrial Sod2. The O2?--dependent suppression of IGF-1 signalling resulted in decreased proliferation of murine dermal fibroblasts, affected translation initiation factors and suppressed the expression of ?1(I), ?1(III), and ?2(I) collagen, the hallmarks of skin ageing. Enhanced O2?- 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 O2?--induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with O2?-, PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies.

SUBMITTER: Singh K 

PROVIDER: S-EPMC4309668 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Singh Karmveer K   Maity Pallab P   Krug Linda L   Meyer Patrick P   Treiber Nicolai N   Lucas Tanja T   Basu Abhijit A   Kochanek Stefan S   Wlaschek Meinhard M   Geiger Hartmut H   Scharffetter-Kochanek Karin K  

EMBO molecular medicine 20150101 1


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 (O2∙-) in mitochondria, either by chemical inhibition of complex I or by  ...[more]

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