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

Autor: Karmveer Singh, Pallab Maity, Linda Krug, Patrick Meyer, Nicolai Treiber, Tanja Lucas, Abhijit Basu, Stefan Kochanek, Meinhard Wlaschek, Hartmut Geiger, Karin Scharffetter‐Kochanek
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 7, Iss 1, Pp 59-77 (2014)
Druh dokumentu: article
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.201404082
Popis: 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 ( O 2 ∙ − ) in mitochondria, either by chemical inhibition of complex I or by genetic silencing of O 2 ∙ − ‐dismutating mitochondrial Sod2. The O 2 ∙ − ‐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 O 2 ∙ − 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 O 2 ∙ − ‐induced IGF‐1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with O 2 ∙ − , PTP1B, and PTEN as promising targets for drug development to prevent IGF‐1 resistance‐related pathologies.
Databáze: Directory of Open Access Journals
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