p53 suppresses carcinoma progression by inhibiting mTOR pathway activation.
p53 suppresses carcinoma progression by inhibiting mTOR pathway activation.
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p53通过抑制MTOR途径激活来抑制癌的进展。
作者：
在人类癌症和小鼠模型中的遗传改变表明，Rb和P53在视网膜母细胞瘤、一种神经源性肿瘤以及包括小细胞肺癌和甲状腺髓样癌(MTC)在内的神经内分泌肿瘤中具有关键的肿瘤抑制功能。Rb失活是视网膜母细胞瘤的始发病变，目前的模型认为诱导细胞凋亡是关键的P53肿瘤抑制功能。然而，对小鼠的遗传学研究表明，其他未明确的p53肿瘤抑制功能在体内也是有效的。P53缺失如何与Rb失活协同促进癌变也不完全清楚。在目前的研究中，基因工程小鼠被用来确定Rb和P53在MTC发病机制中的作用，并验证P53通过抑制mTOR信号来抑制肿瘤发生的假说。有条件的Rb消融导致类似于人类MTC的甲状腺肿瘤，额外的P53缺失导致肿瘤快速进展。P53通过抑制细胞周期进程抑制肿瘤的发生，但不诱导细胞凋亡。相反，P53的缺失导致了细胞凋亡的增加，这是肿瘤进展所必须克服的。MTOR活性在P53缺陷型肿瘤中显着增强，雷帕霉素治疗抑制肿瘤细胞生长，表明mTOR抑制是一种关键的P53肿瘤抑制功能。雷帕霉素治疗没有导致AKT/MAPK激活，这提供了证据，表明这种在其他癌症中起作用的反馈机制不是对mTORC1抑制的一般反应。总之，这些研究提供了基因改变和致癌关键的异常信号通路之间的机制联系，并确定了体内基本的Rb和P53肿瘤抑制功能。
Genetic alterations in human cancers and murine models indicate that Rb and p53 have critical tumor suppressive functions in retinoblastoma, a tumor of neural origin, and neuroendocrine tumors including small cell lung cancer and medullary thyroid cancer (MTC). Rb inactivation is the initiating lesion in retinoblastoma and current models propose that induction of apoptosis is a key p53 tumor suppressive function. Genetic studies in mice, however, indicate that other undefined p53 tumor suppressive functions are operative in vivo. How p53 loss cooperates with Rb inactivation to promote carcinogenesis is also not fully understood. In the current study, genetically engineered mice were generated to determine the role of Rb and p53 in MTC pathogenesis and test the hypothesis that p53 suppresses carcinogenesis by inhibiting mTOR signaling. Conditional Rb ablation resulted in thyroid tumors mimicking human MTC, and additional p53 loss led to rapid tumor progression. p53 suppressed tumorigenesis by inhibiting cell cycle progression, but did not induce apoptosis. On the contrary, p53 loss led to increased apoptosis that had to be overcome for tumor progression. mTOR activity was markedly increased in p53 deficient tumors and rapamycin treatment suppressed tumor cell growth identifying mTOR inhibition as a critical p53 tumor suppressive function. Rapamycin treatment did not result in AKT/MAPK activation providing evidence that this feedback mechanism operative in other cancers is not a general response to mTORC1 inhibition. Together, these studies provide mechanistic links between genetic alterations and aberrant signaling pathways critical in carcinogenesis, and identify essential Rb and p53 tumor suppressive functions in vivo.
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