FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation.
Loss-of-function mutations of phosphatase/tensin homolog deleted on chromosome 10 (PTEN)-induced putative kinase 1 (Pink1) (also known as Park6) identified in familial forms of Parkinson's disease (PD) are associated with compromised mitochondrial function. Emerging data suggest that Pink1 is an essential pro-survival factor that is induced in response to oxidative stress. However, the mechanisms regulating Pink1 expression under stress conditions remain unknown. Forkhead box, subgroup O (FOXO) transcription factors carry out distinct biological functions in response to different extracellular signals. Notably, FOXO factors possess evolutionarily conserved roles in protecting cells from oxidative stress-induced death. Here we report that the FOXO family member FOXO3a controls Pink1 transcription in both mouse and human cells subjected to growth factor deprivation and that this regulation is exerted through evolutionarily conserved FOXO binding elements. Induction of Pink1 by FOXO3a is crucial for survival signals in lymphocytes, as depletion of Pink1 sensitizes these cells to death induced by deprivation of an essential growth factor. Our data reveal that the role of FOXO factors in protecting cells from growth factor deprivation-triggered apoptosis has been underestimated and that FOXOs mediate this protection by transactivating anti-apoptotic effectors like Pink1. Given the essential role of Pink1 in combating cell death, our findings may help to dissect the mechanisms by which FOXO proteins function as anti-oxidative stress factors.
Mei
Yang
Y
Key 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.
Zhang
Yiru
Y
Yamamoto
Kazuo
K
Xie
Wei
W
Mak
Tak W
TW
You
Han
H
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D017124:Conserved Sequence; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D018384:Oxidative Stress; D011494:Protein Kinases / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional; D015533:Transcriptional Activation; D000099202:PTEN-Induced Putative Kinase
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C499517:FOXO3 protein, human; C474033:FoxO3 protein, mouse