The tumorigenic potential and cell growth characteristics of p53-deficient cells are equivalent in the presence or absence of Mdm2
The tumorigenic potential and cell growth characteristics of p53-deficient cells are equivalent in the presence or absence of Mdm2
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DOI：
10.1073/pnas.93.24.14106
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发表时间：
1996-11-26
影响因子：
11.1
通讯作者：
Bradley, A
中科院分区：
文献类型：
--
作者：
Jones, SN;Sands, AT;Bradley, A
Mdm 2癌蛋白与p53肿瘤抑制蛋白形成复合物，并抑制p53介导的异源基因表达调节。最近，已经发现Mdm 2结合几种其他蛋白质，其功能是调节细胞周期进程，包括EZF-1/DP 1转录因子复合物和视网膜母细胞瘤肿瘤抑制蛋白。为了确定Mdm 2是否在细胞周期控制或肿瘤发生中起不同于其调节p53功能的作用，我们已经检查并比较了p53缺陷型和Mdm 2/p53缺陷型成纤维细胞的体外生长特性，以及p53缺陷型和Mdm 2/p53缺陷型小鼠中肿瘤形成的速率和谱，我们发现p53缺陷型成纤维细胞和Mdm 2/p53缺陷型成纤维细胞在培养中的增殖率或在用各种遗传毒性剂处理时的存活频率方面没有差异，细胞周期研究表明，当用DNA处理时，两种细胞群进入S期的能力没有差异。损伤剂或核苷酸抗代谢物，并且p53缺陷型成纤维细胞和Mdm 2/p53缺陷型成纤维细胞在培养物中长期传代后表现出相同的自发永生化速率。最后，p53缺陷型小鼠和Mdm 2/p53缺陷型小鼠在体内表现出相同的自发肿瘤形成的发生率和谱。这些结果表明，当p53不存在时，Mdm 2的缺失对细胞增殖、细胞周期控制或肿瘤发生没有额外的影响。
The Mdm2 oncoprotein forms a complex with the p53 tumor suppressor protein and inhibits p53-mediated regulation of heterologous gene expression. Recently, Mdm2 has been found to bind several other proteins that function to regulate cell cycle progression, including the EZF-1/DP1 transcription factor complex and the retinoblastoma tumor-suppressor protein, To determine whether Mdm2 plays a role in cell cycle control or tumorigenesis that is distinct from its ability to modulate p53 function, we have examined and compared both the in vitro growth characteristics of p53-deficient and Mdm2/p53-deficient fibroblasts, and the rate and spectrum of tumor formation in p53-deficient and Mdm2/p53-deficient mice, We find no difference between p53-deficient fibroblasts and Mdm2/p53-deficient fibroblasts either in their rate of proliferation in culture or in their survival frequency when treated with various genotoxic agents, Cell cycle studies indicate no difference in the ability of the two cell populations to enter S phase when treated with DNA-damaging agents or nucleotide antimetabolites, and p53-deficient fibroblasts and Mdm2/p53-deficient fibroblasts exhibit the same rate of spontaneous immortalization following long-term passage in culture, Finally, p53-dcficient mice and Mdm2/p53-deficient mice display the same incidence and spectrum of spontaneous tumor formation in vivo. These results demonstrate that deletion of Mdm2 has no additional effect on cell proliferation, cell cycle control, or tumorigenesis when p53 is absent.