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

A. Lin, J. Yao, L. Zhuang, D. Wang, J. Han, E. W.F. Lam, B. Gan

    Research output: Contribution to journalArticle

    44 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)3183-3194
    Number of pages12
    JournalOncogene
    Volume33
    Issue number24
    DOIs
    StatePublished - Jun 12 2014

    Keywords

    • BNIP3
    • FoxO
    • energy stress
    • mTORC1

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

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    Lin, A., Yao, J., Zhuang, L., Wang, D., Han, J., Lam, E. W. F., & Gan, B. (2014). The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress. Oncogene, 33(24), 3183-3194. https://doi.org/10.1038/onc.2013.273