TY - JOUR
T1 - The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress
AU - Lin, A.
AU - Yao, J.
AU - Zhuang, L.
AU - Wang, D.
AU - Han, J.
AU - Lam, E. W.F.
AU - Gan, B.
N1 - Funding Information:
We thank Drs Junjie Chen and Hui-Kuan Lin for critical reading of the paper. We also thank Dr Benoit Viollet for providing AMPK WT and KO MEFs and Dr Hsiao-Sheng Liu for providing BNIP3 expression plasmid. BG would also like to thank Ron DePinho for his encouragement and suggestions on this study. This study has been supported by grants from MD Anderson Cancer Center, US Department of Defense (TS093049 and PC100356), LAM Foundation (LAM092P01-12), Concern Foundation and Sidney Kimmel Foundation (to BG) and the TCGA grant U24CA143883 from NCI/NIH (to JY). BG is a Kimmel Scholar and a member of the MD Anderson Cancer Center (CA016672).
PY - 2014/6/12
Y1 - 2014/6/12
N2 - 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. FoxOs inhibit the mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cell growth, under energy stress, and inactivation of FoxOs 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 p38β, 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.
AB - 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. FoxOs inhibit the mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cell growth, under energy stress, and inactivation of FoxOs 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 p38β, 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.
KW - BNIP3
KW - FoxO
KW - energy stress
KW - mTORC1
UR - http://www.scopus.com/inward/record.url?scp=84902458305&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84902458305&partnerID=8YFLogxK
U2 - 10.1038/onc.2013.273
DO - 10.1038/onc.2013.273
M3 - Article
C2 - 23851496
AN - SCOPUS:84902458305
SN - 0950-9232
VL - 33
SP - 3183
EP - 3194
JO - Oncogene
JF - Oncogene
IS - 24
ER -