The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress

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	The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress
	Lin, A. ; Yao, J. ; Zhuang, L. ; Wang, D. ; Han, J. ; Lam, E. W-F ; Gan, B. ; Han JH(韩家淮)
刊名	http://dx.doi.org/10.1038/onc.2013.273
	2014-06-12
关键词	TSC1-TSC2 COMPLEX TUMOR SUPPRESSORS SIGNALING PATHWAY MAMMALIAN TARGET GROWTH-CONTROL NULL-CELLS AMPK METABOLISM LKB1 AUTOPHAGY
英文摘要	MD Anderson Cancer Center, US Department of Defense [TS093049, PC100356]; LAM Foundation [LAM092P01-12]; Concern Foundation; Sidney Kimmel Foundation; TCGA grant from NCI/NIH [U24CA143883]; Normal cells possess adaptive mechanisms to couple energy availability with cell growth (cell size increase) and survival, and imbalances are associated with major diseases such as cancer. Inactivation of critical regulators involved in energy stress response, including adenosine monophosphate-activated protein kinase (AMPK), liver kinase B1 (LKB1), tuberous sclerosis complex 1 (TSC1) and tuberous sclerosis complex 2 (TSC2), leads to uncontrolled cell growth yet increased apoptosis under energy stress. These energy stress regulators are also important in tumor suppression and metabolism. Here, we show that forkhead box O (FoxO) transcription factor, a central regulator of tumor suppression and metabolism, plays a unique role in energy stress response. Fox Os inhibit the mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cell growth, under energy stress, and inactivation of Fox Os alleviates energy stress-mediated mTORC1 repression. Surprisingly, unlike AMPK-, Lkb1- or Tsc1/2-deficient cells, FoxO-deficient cells exhibit decreased apoptosis under energy stress. FoxOs operate to inhibit mTORC1 signaling and cell survival independent of AMPK and TSC. Integrated transcriptomic and functional analyses identified BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)-a negative regulator of both Rheb and Bcl2 prosurvival family members-as a key downstream target of FoxOs to inhibit mTORC1 function and promote apoptosis in response to energy stress. We show that p38 beta, but not AMPK, is likely to function upstream of FoxO-BNIP3 to mediate energy stress response. Finally, we reveal that low expression of FoxO or BNIP3 correlates with poor clinical outcomes in renal cancer patients. Together, our study uncovers a novel signaling circuit functioning to mediate cellular energy responses to control cell growth and survival. These findings also have important implications to human cancers.
语种	英语
出版者	NATURE PUBLISHING GROUP
内容类型	期刊论文
源URL	[http://dspace.xmu.edu.cn/handle/2288/90770]
专题	生命科学－已发表论文
推荐引用方式 GB/T 7714	Lin, A.,Yao, J.,Zhuang, L.,et al. The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress[J]. http://dx.doi.org/10.1038/onc.2013.273,2014.
APA	Lin, A..,Yao, J..,Zhuang, L..,Wang, D..,Han, J..,...&韩家淮.(2014).The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress.http://dx.doi.org/10.1038/onc.2013.273.
MLA	Lin, A.,et al."The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress".http://dx.doi.org/10.1038/onc.2013.273 (2014).