An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2
An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2
复制标题
DOI：
10.1038/sj.onc.1204533
复制
发表时间：
2001-07-05
期刊：
影响因子：
8
通讯作者：
Lozano, G
中科院分区：
文献类型：
--
作者：
Evans, SC;Viswanathan, M;Lozano, G
鼠双微体2（mdm 2）基因的人类对应物hdm 2编码抑制p53肿瘤抑制因子的功能的90-kD蛋白（HDM 2），HDM 2在大约30%的肉瘤中扩增，导致HDM 2的过度产生和p53的失活，使用免疫组织化学筛选一组人类肿瘤的HDM 2过度产生，me在25%的肺肿瘤的细胞质中检测到高水平的HDM 2，而不是其在细胞核中的正常定位。这些样品含有全长hdm 2和几种交替剪接形式的hdm 2 mRNA，序列分析显示p53结合结构域的交替剪接形式的缺失和核定位信号的缺乏。在瞬时转染实验中，HDM 2（ALT 1）是一种选择性剪接形式，它与全长HDM 2在细胞质中结合并隔离。此外，HDM 2（ALT 1）与HDM 2的结合抑制了HDM 2与p53的相互作用，从而增强了p53的转录活性。这些数据表明存在另一种水平的HDM 2调节，其增加了p53的活性。
The human counterpart hdm2 of the murine double-minute 2 (mdm2) gene encodes a 90-kD protein (HDM2) that inhibits the function of the p53 tumor suppressor, Hdm2 is amplified in approximately 30% of sarcomas, leading to overproduction of HDM2 and inactivation of p53, Using immunohistochemistry to screen a panel of human tumors for HDM2 overproduction, me detected high levels of HDM2 in the cytoplasm in 25% of lung tumors as opposed to its normal localization in the nucleus, These samples contained full-length hdm2 and several alternate-splice forms of hdm2 mRNA, Sequence analysis revealed deletions in the alternate-splice forms of the p53 binding domain and absence of a nuclear localization signal. In transient transfection assays, one of the alternate-splice forms, HDM2(ALT1), bound and sequestered full-length HDM2 in the cytoplasm, In addition, the binding of HDM2(ALT1) to HDM2 inhibited the interaction of HDM2 with p53, thus enhancing p53 transcriptional activity, These data suggest the existence of another level of regulation of HDM2 which increases the activity of p53.