细胞可以不可逆地退出细胞周期并进入衰老状态，以阻止无控制的增殖。虽然p53-p21和p16-Rb通路被认为介导衰老，但它们也介导可逆的细胞周期阻滞（休眠），这引发了衰老是否实际上是可逆的问题，或者是衰老相关的不可逆性是通过其他机制来实现的。在这里，我们展示了衰老是不可逆的，并且衰老的承诺和维持是通过不可逆的MYC降解来介导的。当表达一种不可降解的MYC突变体时，衰老细胞开始分裂，而当MYC被沉默时，休眠细胞转变为衰老细胞。在早期口腔癌发生过程中，上皮细胞表现出MYC丧失并变为衰老状态，以防止恶性转化。后期的口腔癌前病变阶段显示出升高的MYC水平和细胞异形性。因此，与衰老相关的不可逆细胞周期退出是通过持续性的MYC降解来介导的，但是绕过这种降解可能允许肿瘤细胞在癌症发生过程中逃逸。Elsevier Inc.出版。

Cells can irreversibly exit the cell cycle and become senescent to safeguard against uncontrolled proliferation. While the p53-p21 and p16-Rb pathways are thought to mediate senescence, they also mediate reversible cell cycle arrest (quiescence), raising the question of whether senescence is actually reversible or whether alternative mechanisms underly the irreversibility associated with senescence. Here, we show that senescence is irreversible and that commitment to and maintenance of senescence are mediated by irreversible MYC degradation. Senescent cells start dividing when a non-degradable MYC mutant is expressed, and quiescent cells convert to senescence when MYC is knocked down. In early oral carcinogenesis, epithelial cells exhibit MYC loss and become senescent as a safeguard against malignant transformation. Later stages of oral premalignant lesions exhibit elevated MYC levels and cellular dysplasia. Thus, irreversible cell cycle exit associated with senescence is mediated by constitutive MYC degradation, but bypassing this degradation may allow tumor cells to escape during cancer initiation.Published by Elsevier Inc.