Superoxide anion radicals induce IGF ‐1 resistance through concomitant activation of PTP 1 B and PTEN
| Autor: | Abhijit Basu, Meinhard Wlaschek, Nicolai Treiber, Stefan Kochanek, Karmveer Singh, Tanja Lucas, Pallab Maity, Hartmut Geiger, Patrick Meyer, Karin Scharffetter-Kochanek, Linda Krug |
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| Rok vydání: | 2014 |
| Předmět: |
Aging
SOD2 phosphatase Receptor IGF Type 1 Mice chemistry.chemical_compound Superoxides Animals Humans Gene silencing PTEN Insulin-Like Growth Factor I Research Articles Tissue homeostasis reactive oxygen species Mice Knockout Protein Tyrosine Phosphatase Non-Receptor Type 1 chemistry.chemical_classification Reactive oxygen species biology Superoxide Dismutase Superoxide Kinase PTEN Phosphohydrolase Mitochondria Cell biology superoxide anions chemistry Biochemistry ageing IGF-1 biology.protein Molecular Medicine Signal transduction Signal Transduction |
| Zdroj: | EMBO Molecular Medicine |
| ISSN: | 1757-4684 1757-4676 |
| DOI: | 10.15252/emmm.201404082 |
| Popis: | 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 α1(I), α1(III), and α2(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. |
| Databáze: | OpenAIRE |
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