Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein
Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein
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DOI：
10.1093/emboj/17.2.554
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发表时间：
1998-01-15
期刊：
影响因子：
11.4
通讯作者：
Levine, AJ
中科院分区：
文献类型：
--
作者：
Roth, J;Dobbelstein, M;Levine, AJ
Hdm2基因在多种人类肿瘤中过表达。它的基因产物主要定位于细胞核，在那里它扮演着p53肿瘤抑制基因产物的抑制剂的角色。结果表明，Hdm2癌蛋白在细胞核和细胞质之间持续穿梭，Hdm2的穿梭不依赖于它与P53的相互作用。Hdm2的核输出是由一个与人类免疫缺陷病毒和其他慢病毒的rev蛋白核输出信号相似的信号序列介导的。该信号序列的突变取消了可检测到的核质穿梭。当与载体蛋白融合时，Hdm2信号序列可以在核内显微注射到HeLa细胞后介导核输出。Hdm2的出口可以被竞争性的转速出口抑制物阻止，理由是Hdm2和Revv的出口途径要么重叠，要么相同。抑制其输出改变了HDM2阻断P53介导的转录激活的能力，而HDM2的S输出功能是加速P53降解所必需的。因此，REV核输出途径可能被用来调节癌基因产物的活性和调节细胞生长。
The hdm2 gene is overexpressed in a variety of human tumors. Its gene product localizes predominantly to the nucleus, where it acts as an inhibitor of the p53 tumor suppressor gene product. It is shown here that the hdm2 oncoprotein constantly shuttles between the nucleus and the cytoplasm, Shuttling of hdm2 does not depend on its interaction with p53. Nuclear export of hdm2 is mediated by a signal sequence similar to the nuclear export signal of the rev protein from human immunodeficiency virus and other lentiviruses. Mutation of this signal sequence abolishes detectable nucleocytoplasmic shuttling. When fused to a carrier protein, the hdm2 signal sequence can mediate nuclear export after intranuclear microinjection into HeLa cells. The export of hdm2 can be blocked by a competitive inhibitor of rev export, arguing that the export pathways for hdm2 and rev are either overlapping or identical. Inhibition of its export modifies the ability of hdm2 to block p53-mediated transcriptional activation, and hdm2's export function is required to accelerate the degradation of p53. Thus the rev nuclear export pathway may be used to regulate an oncogene product's activity and modulate cellular growth.