Hdm2 nuclear export, regulated by insulin-like growth factor-I/MAPK/p90Rsk signaling, mediates the transformation of human cells
Hdm2 nuclear export, regulated by insulin-like growth factor-I/MAPK/p90Rsk signaling, mediates the transformation of human cells
复制标题
DOI：
10.1074/jbc.m511617200
复制
发表时间：
2006-06-16
影响因子：
4.8
通讯作者：
Mayo, Lindsey D.
中科院分区：
文献类型：
--
作者：
Jackson, Mark W.;Patt, Linnea E.;Mayo, Lindsey D.
胰岛素样生长因子(IGF)-I受体的激活通过MAP激酶和磷脂酰肌醇3-激酶信号通路促进细胞增殖和存活。在IGF-I的刺激下，Hdm2癌蛋白被AKT磷酸化，导致其快速的核转位，随后抑制了P53。我们现在发现，IGF-I刺激通过MAP激酶途径调节Hdm2和P53的核输出。通过药物手段抑制p38MAPK或MEK或表达显性负性蛋白可抑制Hdm2的胞浆积聚，增加Hdm2和P53的蛋白水平，而结构性激活的p90Rsk促进Hdm2的核输出。E1a、致癌基因H-RAS和hTERT表达的p90Rsk导致正常人成纤维细胞的非贴壁生长。我们的发现将p90Rsk介导的hdm2核质穿梭与p53调节细胞周期检查点的能力减弱联系在一起，最终导致转化。
Insulin-like growth factor (IGF)-I receptor activation leads to enhanced proliferation and cell survival via the MAP kinase and phosphatidylinositol 3-kinase-signaling pathways. Upon stimulation by IGF-I, the Hdm2 oncoprotein is phosphorylated by AKT, leading to its rapid nuclear translocation and subsequent inhibition of p53. We now show that IGF-I stimulation regulates the nuclear export of Hdm2 and p53 via the MAP kinase pathway. Inhibition of p38 MAPK or MEK via pharmacological means or expression of dominant negative proteins inhibited the cytoplasmic accumulation of Hdm2 and increased Hdm2 and p53 protein levels, whereas constitutively active p90Rsk promoted the nuclear export of Hdm2. Expression of constitutively active p90Rsk with E1A, oncogenic H-Ras, and hTERT resulted in the anchorage-independent growth of normal human fibroblasts. Our findings link p90Rsk-mediated modulation of Hdm2 nuclear to cytoplasmic shuttling with the diminished ability of p53 to regulate cell cycle checkpoints that ultimately leads to transformation.