Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner
Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner
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DOI：
10.1016/j.bbrc.2005.11.148
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发表时间：
2006-02-03
影响因子：
3.1
通讯作者：
Kitagawa, M
中科院分区：
文献类型：
--
作者：
Miwa, S;Uchida, C;Kitagawa, M
Mdm2 促进肿瘤抑制因子 p53 的泛素化，并可通过大幅下调 p53 发挥癌基因的作用。尽管已报道 Mdm2 具有独立于 p53 的作用，但其潜在机制仍不清楚。在本研究中，我们表明 Mdm2 通过下调参与 p53 独立的致癌作用。 pRB。在30例非小细胞肺癌患者中pRB的表达与Mdm2的表达呈明显负相关。在一些p53突变的病例中，Mdm2表达高水平，pRB表达水平低。 Mdm2 在没有野生型 p53 的细胞中促进 pRB 泛素化。此外，缺乏 pRB 泛素化活性的突变体 Mdm2 显着增强了 p53 缺陷细胞系 SRB1 中 pRB 介导的 G1 期停滞。野生型 Mdm2 增加了 p53 敲除 MEF 的软琼脂集落形成活性，但突变型 Mdm2 没有增加。这些发现表明，无论 p53 基因状态如何，Mdm2 的过度表达都会扰乱 RB 通路，从而促进致癌作用。 (c) 2005 Elsevier Inc. 保留所有权利。
Mdm2 promotes ubiquitination of the tumor suppressor p53 and can function as an oncogene by largely downregulating p53. Although a p53-independent role of Mdm2 has been reported, the underlying mechanism remains unclear. In the present study, we indicated that Mdm2 is involved in p53-independent carcinogenesis via downregulation. of pRB. Expression of pRB showed an apparent inverse correlation with Mdm2 expression in 30 patients with non-small cell lung cancer. There were some cases with the p53 mutations in which a high level of Mdm2 and a low level of pRB were expressed. Mdm2 promoted ubiquitination of pRB in cells without wild-type p53. Furthermore, pRB-mediated G1 arrest in a p53-deficient cell line, SRB1, was significantly enhanced by a mutant Mdm2 that lacks pRB ubiquitination activity. Soft-agar colony formation activity of p53-knockout MEF was increased by wild-type Mdm2 but not mutant Mdm2. These findings suggest that overexpression of Mdm2 can perturb a RB pathway regardless of the p53 gene status, promoting carcinogenesis. (c) 2005 Elsevier Inc. All rights reserved.