Editors' ChoiceCell Survival

In the Pink1 with FOXO3a

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Science Signaling  07 Apr 2009:
Vol. 2, Issue 65, pp. ec122
DOI: 10.1126/scisignal.265ec122

Various lines of evidence suggest that Pink1 (PTEN-induced kinase 1), a mitochondrial protein mutated in some forms of Parkinson’s disease, promotes cell survival under conditions of oxidative stress. Thus, Mei et al. were intrigued when microarray analyses identified Pink1 as a potential target of forkhead box, subgroup O (FOXO) transcription factors, which have also been implicated in mediating responses to oxidative stress. Induction of a FOXO3a transgene in a mouse embryo fibroblast line led to increased abundance of Pink1 mRNA, and experiments in mouse T cells and T cell–derived CTLL-2 cells indicated that Pink1 mRNA expression inversely correlated with Akt signaling (which inhibits FOXO). Notably, stimulation of Akt signaling by interleukin-2 (IL-2) decreased Pink1 mRNA abundance, whereas IL-2 deprivation increased it. Moreover, chromatin immunoprecipitation analysis indicated that IL-2 withdrawal promoted FOXO3a association with the Pink1 promoter, and FOXO3a knockdown reduced the increase in Pink1 mRNA abundance produced by IL-2 withdrawal. Sequence analysis revealed that the mouse Pink1 promoter contained putative FOXO-binding elements (FBE), and experiments with luciferase reporter genes confirmed that FOXO3a stimulated transcription through Pink1 promoter FBEs. Similar analyses indicated that the human Pink1 gene, which contained an FBE, was also regulated by Akt-FOXO3a signaling. Pink1 knockdown in CTLL-2 cells increased caspase-3 activation and apoptosis in response to IL-2 withdrawal. Pink1 knockdown also accelerated the decrease in endogenous reduced glutathione (GSH) produced by IL-2 withdrawal, whereas exogenous GSH protected against apoptosis in IL-2–deprived cells regardless of Pink1 knockdown. The authors thus conclude that FOXO3a-dependent induction of Pink1 helps protect lymphocytes from apoptosis after IL-2 deprivation—a role that they speculate may be generalizable to other tissues with growth factor–dependent Akt-FOXO signaling.

Y. Mei, Y. Zhang, K. Yamamoto, W. Xie, T. W. Mak, H. You, FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation. Proc. Natl. Acad. Sci. U.S.A. 106, 5153–5158 (2009). [Abstract] [Full Text]

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