mdm2 is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation
mdm2 is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation
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DOI：
10.1128/mcb.23.2.462-473.2003
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发表时间：
2003-01-01
影响因子：
5.3
通讯作者：
Perry, ME
中科院分区：
文献类型：
--
作者：
Mendrysa, SM;McElwee, MK;Perry, ME
p53肿瘤抑制蛋白的功能必须高度调节，因为p53可以导致细胞死亡并防止肿瘤发生。在培养的细胞中，p90（MDM 2）蛋白阻断p53的转录激活结构域，并且还刺激p53的降解。在这里，我们提供了第一个确凿的证据，p90（MDM 2）组成型调节p53活性的稳态组织。带有mdm2亚型等位基因的小鼠揭示了mdm2在淋巴细胞生成和上皮细胞存活中迄今未知的作用。表型分析显示，在这些小鼠中，p53的转录激活和凋亡功能均增加。但p53蛋白水平并没有协同增加，提示p90（MDM 2）可以抑制p53的转录激活和凋亡功能，而不依赖于降解。Cre介导的mdm2缺失导致p53的更大积累，表明p90（MDM2）组成型调节稳态组织中p53的活性和水平。只有一个子集的组织与激活的p53经历细胞凋亡的观察表明，其他因素而不是p90（MDM 2）决定的生理后果p53激活。此外，mdm2在体内的减少导致放射敏感性，突出了mdm2作为辅助癌症治疗的潜在靶点的重要性。
The function of the p53 tumor suppressor protein must be highly regulated because p53 can cause cell death and prevent tumorigenesis. In cultured cells, the p90(MDM2) protein blocks the transcriptional activation domain of p53 and also stimulates the degradation of p53. Here we provide the first conclusive demonstration that p90(MDM2) constitutively regulates p53 activity in homeostatic tissues. Mice with a hypomorphic allele of mdm2 revealed a heretofore unknown role for mdm2 in lymphopoiesis and epithelial cell survival. Phenotypic analyses revealed that both the transcriptional activation and apoptotic functions of p53 were increased in these mice. However, the level of p53 protein was not coordinately increased, suggesting that p90(MDM2) can inhibit the transcriptional activation and apoptotic functions of p53 in a manner independent of degradation. Cre-mediated deletion of mdm2 caused a greater accumulation of p53, demonstrating that p90(MDM2) constitutively regulates both the activity and the level of p53 in homeostatic tissues. The observation that only a subset of tissues with activated p53 underwent apoptosis indicates that factors other than p90(MDM2) determine the physiological consequences of p53 activation. Furthermore, reduction of mdm2 in vivo resulted in radiosensitivity, highlighting the importance of mdm2 as a potential target for adjuvant cancer therapies.