PTEN regulates Mdm2 expression through the P1 promoter
PTEN regulates Mdm2 expression through the P1 promoter
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DOI：
10.1074/jbc.m401488200
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发表时间：
2004-07-09
影响因子：
4.8
通讯作者：
Wu, H
中科院分区：
文献类型：
--
作者：
Chang, CJ;Freeman, DJ;Wu, H
MDM 2是一种通过p53依赖性和非依赖性机制控制肿瘤发生的癌蛋白。Mdm 2 mRNA水平受p53转录调控以响应应激如DNA损伤，其蛋白水平和亚细胞定位受AKT丝氨酸/苏氨酸激酶的后调节。以前的研究表明，PTEN，一种拮抗磷脂酰肌醇3-激酶/ AKT信号传导的双特异性磷酸酶，能够阻断MDM 2核转位并使MDM 2蛋白不稳定。从我们目前的研究结果表明，在调节MDM 2功能的PTEN的额外作用; PTEN调节MDM 2转录和亚型选择负调节其P1启动子。在Pten缺失细胞系和前列腺癌组织中，Mdm 2 P1启动子活性上调，导致L-Mdm 2表达增加和p90（MDM 2）亚型产生增强。此外，PTEN通过其脂质磷酸酶活性控制Mdm 2 P1启动子活性，而不依赖于p53。因此，我们的研究结果提供了一个新的机制，PTEN在控制MDM 2癌蛋白的功能。
MDM2 is an oncoprotein that controls tumorigenesis through both p53-dependent and - independent mechanisms. Mdm2 mRNA level is transcriptionally regulated by p53 in response to stress such as DNA damage, and its protein level and subcellular localization are post-translationally modulated by the AKT serine/threonine kinase. Previous studies showed that PTEN, a dual specificity phosphatase that antagonizes phosphatidylinositol 3-kinase/ AKT signaling, is capable of blocking MDM2 nuclear translocation and destabilizing the MDM2 protein. Results from our current study demonstrate an additional role for PTEN in regulating MDM2 functions; PTEN modulates Mdm2 transcription and isoform selection by negatively regulating its P1 promoter. In Pten-null cell lines and prostate cancer tissues, Mdm2 P1 promoter activity is up-regulated, resulting in increased L-Mdm2 expression and enhanced p90(MDM2) isoform production. Furthermore, PTEN controls Mdm2 P1 promoter activity through its lipid phosphatase activity, independent of p53. Thus, our results provide a novel mechanism for PTEN in controlling MDM2 oncoprotein functions.