Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53
Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53
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DOI：
10.1038/sj.emboj.7601900
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发表时间：
2007-11-01
期刊：
影响因子：
11.4
通讯作者：
Guan, Kun-Liang
中科院分区：
文献类型：
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作者：
Lee, Chung-Han;Inoki, Ken;Guan, Kun-Liang
生长和增殖与细胞应激反应的不协调可导致肿瘤的发生。哺乳动物雷帕霉素靶标(MTOR)是一种中枢细胞生长调控因子，在某些恶性肿瘤中高度激活，其临床意义正在广泛研究中。我们发现，结构性mTOR活性通过刺激p53的翻译，在体外和体内都能放大p53的激活。因此，mTOR的负调控因子TSC1或TSC2的缺失会导致应激条件下P53蛋白的大量积聚和细胞凋亡。换句话说，mTOR的失活通过p53防止了营养胁迫和基因组损伤导致的细胞死亡。我们还一致地表明，P53在TSC肿瘤中升高，这种肿瘤很少变得恶性。MTOR和P53在细胞应激过程中的协调关系为包括TSC在内的错构瘤综合征的良性本质提供了可能的解释。临床上，mTOR抑制剂在抗肿瘤治疗中的疗效可能还取决于P53的状态，mTOR抑制剂可能拮抗遗传毒性化疗药物的作用。
Miscoordination of growth and proliferation with the cellular stress response can lead to tumorigenesis. Mammalian target of rapamycin ( mTOR), a central cell growth controller, is highly activated in some malignant neoplasms, and its clinical implications are under extensive investigation. We show that constitutive mTOR activity amplifies p53 activation, in vitro and in vivo, by stimulating p53 translation. Thus, loss of TSC1 or TSC2, the negative regulators of mTOR, results in dramatic accumulation of p53 and apoptosis in response to stress conditions. In other words, the inactivation of mTOR prevents cell death by nutrient stress and genomic damage via p53. Consistently, we also show that p53 is elevated in TSC tumors, which rarely become malignant. The coordinated relationship between mTOR and p53 during cellular stress provides a possible explanation for the benign nature of hamartoma syndromes, including TSC. Clinically, this also suggests that the efficacy of mTOR inhibitors in anti- neoplastic therapy may also depend on p53 status, and mTOR inhibitors may antagonize the effects of genotoxic chemotherapeutics.