Overexpression of MDM2, due to enhanced translation, results in inactivation of wild-type p53 in Burkitt's lymphoma cells
Overexpression of MDM2, due to enhanced translation, results in inactivation of wild-type p53 in Burkitt's lymphoma cells
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DOI：
10.1038/sj.onc.1201702
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发表时间：
1998-03-26
期刊：
影响因子：
8
通讯作者：
Wiels, J
中科院分区：
文献类型：
--
作者：
Capoulade, C;Bressac-de Paillerets, B;Wiels, J
许多研究表明，p53的失活是肿瘤细胞无限制生长的基本要求之一，当在各种类型的淋巴恶性肿瘤中检查p53基因的状态时，在伯基特淋巴瘤（BL）细胞中主要检测到p53的突变，因此表明p53的改变可以特异性地促成这些肿瘤细胞的恶性表型，除了突变之外，p53的功能失活也可以通过野生型基因产物与各种病毒或细胞蛋白质的相互作用而发生。例如，细胞MDM 2蛋白能够通过隐藏其反式激活结构域来抑制p53肿瘤抑制功能，Mdm 2基因扩增已在几种类型的肉瘤中描述，导致MDM 2蛋白的过表达，在这项研究中，我们检测了20个BL细胞系中MDM 2和p53的状态，发现4个含有野生型p53并过表达MDM 2蛋白。在这些BL细胞中，两种分子物理上结合，因为它们可以共沉淀，并且p53被灭活，因为细胞在γ-辐射后既不停滞在G1期也不进入凋亡。我们还报道了BL细胞中高水平的MDM 2蛋白既不与mdm 2基因的扩增相关，也不与RNA水平的升高或蛋白质稳定性的增加相关，而是由于mdm 2 RNA的翻译能力增强。这些结果表明，在某些BL细胞中，在转录后水平调节的MDM 2蛋白的过表达，诱导逃避p53控制的细胞生长。
Numerous studies have indicated that inactivation of p53 is one of the essential requirements for the unrestrained growth of tumoral cells, When the status of the p53 gene was examined in various types of lymphoid malignancies, mutations in p53 have been predominantly detected in Burkitt's lymphoma (BL) cells, therefore suggesting that alteration of p53 could specifically contribute to the malignant phenotype of these tumoral cells, In addition to mutations, functional inactivation of p53 can also occur through interaction of the wild-type gene product with various viral or cellular proteins, The cellular MDM2 protein, for example, is able to inhibit p53 tumor suppressor function by concealing its transactivation domain, Mdm2 gene amplification has been described in several types of sarcomas, resulting in overexpression of the MDM2 protein, In this study, we have examined the status of MDM2 and p53 in 20 BL cell lines, Four were found to contain wild-type p53 and to overexpress MDM2 protein, Within these BL cells, both molecules are physically associated since they can be co-precipitated and p53 is inactivated as cells neither arrest in G1 nor enter apoptosis following gamma-radiation. We also report that the high level of the MDM2 protein in BL cells is neither associated with an amplification of the mdm2 gene nor with an elevated level of RNA or an increased protein stability, but is rather due to an enhanced translation ability of the mdm2 RNA, These results indicate that in certain BL cells, overexpression of MDM2 protein regulated at the posttranscriptional level, induces an escape from p53-controlled cell growth.