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PNAS 106 (13): 5153-5158

Copyright © 2009 by the National Academy of Sciences.


FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation

Yang Meia,1, Yiru Zhanga,1, Kazuo Yamamotob, Wei Xiea, Tak W. Makb,2, and Han Youa,2

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.

Abstract: 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.

Key Words: apoptosis • oxidative stress • transcription

Freely available online through the PNAS open access option.

Author contributions: T.W.M. and H.Y. designed research; Y.M., Y.Z., K.Y., W.X., and H.Y. performed research; Y.M., Y.Z., and H.Y. analyzed data; and H.Y. wrote the paper.

1Y.M. and Y.Z. contributed equally to this work.

The authors declare no conflict of interest.

This article contains supporting information online at

2To whom correspondence may be addressed. E-mail: tmak{at} or hyou{at}

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J. Biol. Chem. 288, 8491-8504
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N. Dehorter, N. Lozovaya, B. J. Mdzomba, F. J. Michel, C. Lopez, V. Tsintsadze, T. Tsintsadze, M. Klinkenberg, S. Gispert, G. Auburger, et al. (2012)
J. Neurosci. 32, 18047-18053
   Abstract »    Full Text »    PDF »
Programmed Cell Death in Parkinson's Disease.
K. Venderova and D. S. Park (2012)
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Lysine methylation of FOXO3 regulates oxidative stress-induced neuronal cell death.
Q. Xie, Y. Hao, L. Tao, S. Peng, C. Rao, H. Chen, H. You, M.-q. Dong, and Z. Yuan (2012)
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   Abstract »    Full Text »    PDF »
Regulation of neuroblastoma differentiation by forkhead transcription factors FOXO1/3/4 through the receptor tyrosine kinase PDGFRA.
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   Abstract »    Full Text »    PDF »
PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function.
F. Billia, L. Hauck, F. Konecny, V. Rao, J. Shen, and T. W. Mak (2011)
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   Abstract »    Full Text »    PDF »
FoxO Transcription Factors Promote Cardiomyocyte Survival upon Induction of Oxidative Stress.
A. Sengupta, J. D. Molkentin, J.-H. Paik, R. A. DePinho, and K. E. Yutzey (2011)
J. Biol. Chem. 286, 7468-7478
   Abstract »    Full Text »    PDF »
Cancer Cell Metabolism.
R. A. Cairns, I. Harris, S. McCracken, and T. W. Mak (2011)
Cold Spring Harb Symp Quant Biol 76, 299-311
   Abstract »    Full Text »    PDF »
A pivotal role for PINK1 and autophagy in mitochondrial quality control: implications for Parkinson disease.
C. T. Chu (2010)
Hum. Mol. Genet.
   Abstract »    Full Text »    PDF »
Glucocorticoid-induced Leucine Zipper (GILZ) Promotes the Nuclear Exclusion of FOXO3 in a Crm1-dependent Manner.
P. Latre de Late, A. Pepin, H. Assaf-Vandecasteele, C. Espinasse, V. Nicolas, M.-L. Asselin-Labat, J. Bertoglio, M. Pallardy, and A. Biola-Vidamment (2010)
J. Biol. Chem. 285, 5594-5605
   Abstract »    Full Text »    PDF »
PINK1 function in health and disease.
E. Deas, H. Plun-Favreau, and N. W. Wood (2009)
EMBO Mol Med. 1, 152-165
   Abstract »    Full Text »    PDF »

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