Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, 727 Jing Ming Nan Road, Kunming 650500, China.
Int J Mol Sci. 2023 Feb 14;24(4):3790. doi: 10.3390/ijms24043790.
One of the key steps in tumorigenic transformation is immortalization in which cells bypass cancer-initiating barriers such as senescence. Senescence can be triggered by either telomere erosion or oncogenic stress (oncogene-induced senescence, OIS) and undergo p53- or Rb-dependent cell cycle arrest. The tumor suppressor p53 is mutated in 50% of human cancers. In this study, we generated p53N236S (p53S) mutant knock-in mice and observed that p53S heterozygous mouse embryonic fibroblasts () escaped HRas-induced senescence after subculture in vitro and formed tumors after subcutaneous injection into severe combined immune deficiency (SCID) mice. We found that p53S increased the level and nuclear translocation of PGC-1α in late-stage +Ras cells (LS cells, which bypassed the OIS). The increase in PGC-1α promoted the biosynthesis and function of mitochondria in LS cells by inhibiting senescence-associated reactive oxygen species (ROS) and ROS-induced autophagy. In addition, p53S regulated the interaction between PGC-1α and PPARγ and promoted lipid synthesis, which may indicate an auxiliary pathway for facilitating cell escape from aging. Our results illuminate the mechanisms underlying p53S mutant-regulated senescence bypass and demonstrate the role played by PGC-1α in this process.
肿瘤发生转化的关键步骤之一是永生化，在此过程中，细胞绕过衰老等致癌起始障碍。衰老可以由端粒磨损或致癌应激（oncogene-induced senescence，OIS）触发，并经历 p53 或 Rb 依赖性细胞周期停滞。肿瘤抑制因子 p53 在 50%的人类癌症中发生突变。在这项研究中，我们生成了 p53N236S（p53S）突变敲入小鼠，并观察到 p53S 杂合子小鼠胚胎成纤维细胞（MEFs）在体外传代后逃避 HRas 诱导的衰老，并在皮下注射到严重联合免疫缺陷（SCID）小鼠后形成肿瘤。我们发现 p53S 增加了晚期 +Ras 细胞（LS 细胞，绕过 OIS）中 PGC-1α 的水平和核易位。PGC-1α 的增加通过抑制衰老相关的活性氧（ROS）和 ROS 诱导的自噬来促进 LS 细胞中线粒体的生物合成和功能。此外，p53S 调节 PGC-1α 和 PPARγ 之间的相互作用并促进脂质合成，这可能表明促进细胞逃避衰老的辅助途径。我们的结果阐明了 p53S 突变体调节的衰老旁路的机制，并证明了 PGC-1α 在这个过程中的作用。
