Nieminen Anna-Liisa, Qanungo Suparna, Schneider Elizabeth A, Jiang Bing-Hua, Agani Faton H
Department of Anatomy and Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
J Cell Physiol. 2005 Aug;204(2):364-9. doi: 10.1002/jcp.20406.
The interaction between HIF-1alpha, Mdm2, and p53 proteins during hypoxia has received recent attention. Here, we investigated the consequences of interaction between HIF-1alpha and Mdm2 under hypoxic conditions. Endogenous HIF-1alpha and Mdm2 proteins were co-immunoprecipitated from lysates of hypoxic HCT116 p53WT and p53(-/-) cells, suggesting that association of these two proteins is a p53-independent event. The cellular Mdm2 protein content was not significantly altered in hypoxic tumor cells. Overexpression of Mdm2 resulted in an increase in HIF-1alpha protein content in hypoxic cells and increased hypoxia-induced vascular endothelial growth factor (VEGF) transcriptional activation. These results point toward a novel and p53-independent function of Mdm2 to promote tumor cell adaptations to hypoxia by interacting with and promoting HIF-1 activation.
缺氧条件下HIF-1α、Mdm2和p53蛋白之间的相互作用近来受到关注。在此，我们研究了缺氧条件下HIF-1α与Mdm2相互作用的后果。从缺氧的HCT116 p53WT和p53(-/-)细胞裂解物中共同免疫沉淀内源性HIF-1α和Mdm2蛋白，表明这两种蛋白的结合是一个不依赖p53的事件。缺氧肿瘤细胞中细胞Mdm2蛋白含量没有显著改变。Mdm2的过表达导致缺氧细胞中HIF-1α蛋白含量增加，并增强缺氧诱导的血管内皮生长因子（VEGF）转录激活。这些结果表明Mdm2具有一种新的、不依赖p53的功能，即通过与HIF-1相互作用并促进其激活来促进肿瘤细胞适应缺氧。
