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FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation
Tak W. Makb,2, and
aKey Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, 422 South Siming Road, Xiamen, Fujian 361005, China; and bThe Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, Toronto, ON, Canada M5G 2C1
Contributed by Tak W. Mak, February 3, 2009
Received for publication December 9, 2008.
Loss-of-function mutations of phosphatase/tensin homolog deletedon chromosome 10 (PTEN)-induced putative kinase 1 (Pink1) (alsoknown as Park6) identified in familial forms of Parkinson'sdisease (PD) are associated with compromised mitochondrial function.Emerging data suggest that Pink1 is an essential pro-survivalfactor that is induced in response to oxidative stress. However,the mechanisms regulating Pink1 expression under stress conditionsremain unknown. Forkhead box, subgroup O (FOXO) transcriptionfactors carry out distinct biological functions in responseto different extracellular signals. Notably, FOXO factors possessevolutionarily conserved roles in protecting cells from oxidativestress-induced death. Here we report that the FOXO family memberFOXO3a controls Pink1 transcription in both mouse and humancells subjected to growth factor deprivation and that this regulationis exerted through evolutionarily conserved FOXO binding elements.Induction of Pink1 by FOXO3a is crucial for survival signalsin lymphocytes, as depletion of Pink1 sensitizes these cellsto death induced by deprivation of an essential growth factor.Our data reveal that the role of FOXO factors in protectingcells from growth factor deprivation-triggered apoptosis hasbeen underestimated and that FOXOs mediate this protection bytransactivating anti-apoptotic effectors like Pink1. Given theessential role of Pink1 in combating cell death, our findingsmay help to dissect the mechanisms by which FOXO proteins functionas anti-oxidative stress factors.
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