Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA.
Department of Medicinal and Biological Chemistry, University of Toledo, Toledo, Ohio, USA.
J Biol Chem. 2021 Dec;297(6):101365. doi: 10.1016/j.jbc.2021.101365. Epub 2021 Oct 30.
p53 is a well-established critical cell cycle regulator. By inducing transcription of the gene encoding p21, p53 inhibits cyclin-dependent kinase (CDK)-mediated phosphorylation of cell cycle inhibitor retinoblastoma (RB) proteins. Phosphorylation of RB releases E2F transcription factor proteins that transactivate cell cycle-promoting genes. Here, we sought to uncover the contribution of p53, p21, CDK, RB, and E2F to the regulation of ferroptosis, an oxidative form of cell death. Our studies have uncovered unexpected complexity in this regulation. First, we showed that elevated levels of p53 enhance ferroptosis in multiple inducible and isogenic systems. On the other hand, we found that p21 suppresses ferroptosis. Elevation of CDK activity also suppressed ferroptosis under conditions where p21 suppressed ferroptosis, suggesting that the impact of p21 must extend beyond CDK inhibition. Furthermore, we showed that overexpression of E2F suppresses ferroptosis in part via a p21-dependent mechanism, consistent with reports that this transcription factor can induce transcription of p21. Finally, deletion of RB genes enhanced ferroptosis. Taken together, these results show that signals affecting ferroptotic sensitivity emanate from multiple points within the p53 tumor suppressor pathway.
p53 是一种成熟的细胞周期关键调控因子。通过诱导编码 p21 的基因转录，p53 抑制细胞周期蛋白依赖性激酶 (CDK) 介导的细胞周期抑制剂视网膜母细胞瘤 (RB) 蛋白磷酸化。RB 的磷酸化释放出 E2F 转录因子蛋白，这些蛋白可激活促进细胞周期的基因。在这里，我们试图揭示 p53、p21、CDK、RB 和 E2F 对铁死亡（一种氧化形式的细胞死亡）调控的贡献。我们的研究揭示了这种调控的意外复杂性。首先，我们表明高水平的 p53 可增强多种诱导性和同基因系统中的铁死亡。另一方面，我们发现 p21 抑制铁死亡。在 p21 抑制铁死亡的情况下，提高 CDK 活性也抑制铁死亡，这表明 p21 的影响必须超出 CDK 抑制的范围。此外，我们表明 E2F 的过表达部分通过 p21 依赖的机制抑制铁死亡，这与该转录因子可诱导 p21 转录的报告一致。最后，RB 基因的缺失增强了铁死亡。综上所述，这些结果表明，影响铁死亡敏感性的信号源自 p53 肿瘤抑制途径中的多个点。
