The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress.
The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress.
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正常细胞具有将能量可用性与细胞生长（细胞大小增加）和存活相结合的适应机制，而不平衡与癌症等重大疾病有关。失活的关键调节参与能量应激反应，包括AMPK，LKB 1，TSC 1和TSC 2，导致不受控制的细胞生长，但增加细胞凋亡下的能量应激。这些能量应激调节剂在肿瘤抑制和代谢中也很重要。在这里，我们表明，FoxO转录因子，肿瘤抑制和代谢的中央调节器，在能量应激反应中起着独特的作用。在能量应激下，FoxOs抑制mTORC 1，这是细胞生长的关键调节因子，并且FoxOs的失活加剧了能量应激介导的mTORC 1抑制。令人惊讶的是，与AMPK、Lkb 1或Tsc 1/2缺陷型细胞不同，FoxO缺陷型细胞在能量应激下表现出凋亡减少。FoxOs的作用是抑制mTORC 1信号传导和细胞存活，而不依赖于AMPK和TSC。综合转录组学和功能分析鉴定了BNIP 3-Rheb和Bcl 2促生存家族成员的负调节因子-作为FoxOs的关键下游靶点，以抑制mTORC 1功能并促进细胞凋亡以响应能量应激。我们发现p38β，而不是AMPK，可能在FoxO-BNIP 3的上游起作用，介导能量应激反应。最后，我们揭示了FoxO或BNIP 3的低表达与肾癌患者的不良临床结局相关。总之，我们的研究揭示了一种新的信号通路，其功能是介导细胞能量反应以控制细胞生长和存活。这些发现对人类癌症也有重要意义。
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 AMPK, LKB1, TSC1, and 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 FoxO transcription factor, a central regulator of tumor suppression and metabolism, plays a unique role in energy stress response. FoxOs inhibit 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 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.
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影响因子：
4.8
作者：
Khatri, Shikha;Yepiskoposyan, Hasmik;Plas, David R.
通讯作者：
Plas, David R.
影响因子：
12.4
作者：
Davila, D.;Connolly, N. M. C.;Prehn, J. H. M.
通讯作者：
Prehn, J. H. M.
影响因子：
50.3
作者：
Gan B;Lim C;Chu G;Hua S;Ding Z;Collins M;Hu J;Jiang S;Fletcher-Sananikone E;Zhuang L;Chang M;Zheng H;Wang YA;Kwiatkowski DJ;Kaelin WG Jr;Signoretti S;DePinho RA
通讯作者：
DePinho RA
DOI：
10.1073/pnas.151033798
发表时间：
2001-07-17
影响因子：
11.1
作者：
Kobayashi, T;Minowa, O;Hino, O
通讯作者：
Hino, O
影响因子：
4.8
作者：
Greer, Eric L.;Oskoui, Philip R.;Brunet, Anne
通讯作者：
Brunet, Anne