Children's Medical Research Institute, University of Sydney, Sydney, New South Wales, Australia.
Oncogene. 2013 Feb 14;32(7):827-36. doi: 10.1038/onc.2012.102. Epub 2012 Apr 9.
The tumor suppressor protein, p53 is one of the most important cellular defences against malignant transformation. In response to cellular stressors p53 can induce apoptosis, cell cycle arrest or senescence as well as aid in DNA repair. Which p53 function is required for tumor suppression is unclear. The proline-rich domain (PRD) of p53 (residues 58-101) has been reported to be essential for the induction of apoptosis. To determine the importance of the PRD in tumor suppression in vivo we previously generated a mouse containing a 33-amino-acid deletion (residues 55-88) in p53 (mΔpro). We showed that mΔpro mice are protected from T-cell tumors but not late-onset B-cell tumors. Here, we characterize the functionality of the PRD and show that it is important for mediating the p53 response to DNA damage induced by γ-radiation, but not the p53-mediated responses to Ha-Ras expression or oxidative stress. We conclude that the PRD is important for receiving incoming activating signals. Failure of PRD mutants to respond to the activating signaling produced by DNA damage leads to impaired downstream signaling, accumulation of mutations, which potentially leads to late-onset tumors.
肿瘤抑制蛋白 p53 是细胞抵抗恶性转化最重要的防御机制之一。细胞应激时，p53 可以诱导细胞凋亡、细胞周期阻滞或衰老，同时帮助修复 DNA。p53 发挥哪种功能抑制肿瘤尚不明确。p53 的脯氨酸富集结构域（PRD）（残基 58-101）对于诱导细胞凋亡至关重要。为了确定 PRD 在体内抑制肿瘤中的重要性，我们之前生成了一种 p53 缺失 33 个氨基酸（残基 55-88）的小鼠（mΔpro）。我们发现 mΔpro 小鼠可以抵抗 T 细胞肿瘤，但不能抵抗晚期 B 细胞肿瘤。在此，我们研究了 PRD 的功能，并发现它对于介导 p53 对 γ 射线诱导的 DNA 损伤的反应很重要，但对于 p53 介导的对 Ha-Ras 表达或氧化应激的反应不重要。我们的结论是，PRD 对于接收传入的激活信号很重要。PRD 突变体不能对 DNA 损伤产生的激活信号做出反应，导致下游信号转导受损，积累突变，从而导致晚期肿瘤的发生。
