Translational enhancement of mdm2 oncogene expression in human tumor cells containing a stabilized wild-type p53 protein.
Translational enhancement of mdm2 oncogene expression in human tumor cells containing a stabilized wild-type p53 protein.
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发表时间：
1997-08
期刊：
影响因子：
11.2
通讯作者：
J. Landers;S. Cassel;D. George
中科院分区：
文献类型：
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作者：
J. Landers;S. Cassel;D. George
mdm 2癌基因具有转化潜能，可通过过表达激活。我们以前曾报道过人绒毛膜癌细胞系的鉴定，这些细胞系具有非常高水平的mdm 2蛋白以及升高水平的稳定野生型p53蛋白。重要的是，这种mdm 2过表达是由mdm 2 mRNA翻译增强引起的，这是一种以前没有涉及mdm 2表达控制的机制。本研究的重点是研究mdm 2 mRNA在人类癌症中增强翻译的广度，并阐明这种翻译激活的基础。在这里，我们提出的证据表明，mdm 2表达的翻译增强发生在各种人类肿瘤细胞。这些样本中的大多数也具有高水平的野生型p53蛋白。然而，没有证据表明p53靶基因p21/waf 1和gadd 45同时过表达。此外，我们证明，mdm 2的翻译增强涉及mdm 2转录的优先增加，这是从该基因的内部p53响应启动子区域启动。产生的特定mdm 2转录物含有独特的5'非翻译区，并表现出显著增强的翻译效率。这些数据为mdm 2蛋白在这类人类肿瘤中的过度表达提供了定量解释。
The mdm2 oncogene has transforming potential that is activated by overexpression. We previously reported the identification of human choriocarcinoma cell lines that have very high levels of mdm2 proteins as well as elevated levels of a stabilized wild-type p53 protein. Importantly, this mdm2 overexpression resulted from enhanced translation of mdm2 mRNA, a mechanism that had not previously been implicated in mdm2 expression control. The focus of this study was to investigate the breadth of enhanced translation of mdm2 mRNA in human cancers and to elucidate the basis for this translational activation. Here we present evidence that translational enhancement of mdm2 expression occurs in a variety of human tumor cells. Most of these samples also have high levels of wild-type p53 protein. However, there is no evidence for concomitant overexpression of the p53 target genes p21/waf1 and gadd45. Additionally, we demonstrate that the translational enhancement of mdm2 involves a preferential increase in mdm2 transcription that is initiated from the internal p53-responsive promoter region of this gene. The particular mdm2 transcripts that are generated contain a distinct 5' untranslated region and exhibit a significantly enhanced translational efficiency. These data provide a quantitative explanation for the overexpression of mdm2 proteins in this class of human tumors.