p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM (Nat Cell Biol, 2007, 9:573-580)

報告日期: 2007/11/23
報告時間: 16:00/16:50
報告學生: 溫凡志
講評老師: 黃溫雅


p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM

Nature Cell Biology, Vol. 9, 573-580, May, 2007
















In the past, p53 has been identified as a tumor suppressor in regulating cell-cycle, apoptosis, senescence and differentiation. The p53 mutations occurred in about half of human cancers, and p53 mutants not only loss of tumor suppression activities but gain of novel functions. Somatic p53 mutants were proposed to gain oncogenic activities in promoting tumor progress and resistance to cytotoxic drugs. There were usually four hot spot mutations (175, 248, 249, and 273) of p53 found in clinical patients, and p53R248W and p53R273H mutations have been reported to induce conformational changes and to abolish the tumor suppression activities. In this study, in order to demonstrate that how p53 gain-of-function mutants abolished tumor suppression functions and promoted tumorigensis, a humanized p53 knock-in (HUPKI) mice with mutants (R248W) was generated. In p53R248W MEFs, the mutant p53 performed more stable than wild type after UV irradiation and seemed to escape ubiquitination by Mdm2. The p53-dependent overexpression including p21 and Mdm2 was abolished to suggest that p53 mutants lost the wild-type transcriptional activities after DNA damage. In p53R248W mice thymocytes, the frequency of interchromosomal translocation was higher than that of p53-/- cells, and G2-M checkpoint was impaired in p53 mutant cells after DNA damage. The oncogenic p53 mutants were explained by that mutants interact with the nuclease Mre11 to suppress the binding of the Mre11–Rad50–NBS1 (MRN) complex to DNA double-stranded breaks and resulted in reduced ATM activation. Therefore, p53 gain-of-function cancer mutants promote tumorigenesis by a novel mechanism involving the disruption of DNA damage-response pathways.



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