Smith M L
Indiana University Cancer Center, Department of Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, USA.
Breast Cancer Res Treat. 1999 Nov;58(2):99-105. doi: 10.1023/a:1006390107197.
Overexpression of Mdm2 in cancer cells with otherwise wild-type p53 is believed to be an alternative mechanism for p53 inactivation during carcinogenesis. Because a number of genetic alterations that inactivate p53, including mutation, homozygous deletion, or viral oncoprotein expression (e.g. HPV16-E6), inhibit DNA repair, we tested the hypothesis that Mdm2 would likewise inhibit DNA repair. Repair of cisplatin-induced DNA damage was reduced in MCF7 cells overexpressing Mdm2, compared to MCF7 cells in which wild-type p53 function was intact. MCF7-Mdm2 cells exhibited preferential sensitivity to cisplatin and carboplatin. MCF7-Mdm2 cells showed a pronounced S-phase arrest after cisplatin treatment, similar to that observed in mutant-p53 cells in the present and prior studies. MCF7 cells with intact wild-type p53, on the other hand, arrested primarily in G2/M phase after cisplatin treatment. These findings indicate that Mdm2 overexpression can recapitulate the effect of p53 mutations on DNA repair of cisplatin lesions.
在具有野生型p53的癌细胞中，Mdm2的过表达被认为是致癌过程中p53失活的另一种机制。由于许多使p53失活的基因改变，包括突变、纯合缺失或病毒癌蛋白表达（如HPV16 - E6），都会抑制DNA修复，我们测试了Mdm2同样会抑制DNA修复的假设。与野生型p53功能完整的MCF7细胞相比，过表达Mdm2的MCF7细胞中顺铂诱导的DNA损伤修复减少。MCF7 - Mdm2细胞对顺铂和卡铂表现出优先敏感性。顺铂处理后，MCF7 - Mdm2细胞出现明显的S期阻滞，类似于本研究及以往研究中在突变型p53细胞中观察到的情况。另一方面，野生型p53功能完整的MCF7细胞在顺铂处理后主要阻滞在G2/M期。这些发现表明，Mdm2过表达可重现p53突变对顺铂损伤DNA修复的影响。
