期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 278, 期 32, 页码 30125-30135出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M302042200
关键词
-
Tumors utilize hyperactivation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway to cope with deleterious environmental conditions. Activation of the PI3K/AKT pathway has been shown to increase protein expression of the alpha subunit of the hypoxia-inducible factor (HIF) 1, a key regulator of oxygen homeostasis. Elevated levels of HIF-1alpha induce expression of genes with critical roles in angiogenesis, erythropoiesis, and glucose metabolism, processes that are essential for tumor expansion. Here we examine the involvement of FOXO4 (also known as AFX), a member of the forkhead transcription factor superfamily that is negatively regulated by the PI3K/AKT pathway, in the regulation of HIF-1alpha protein expression. Nuclear expression of FOXO4 results in the suppression of various responses to hypoxia, including decreased vascular endothelial growth factor, glucose transporter 1, and erythropoietin expression. Interestingly, FOXO4 down-regulates the HIF-1alpha protein levels, consistent with the lack of hypoxia responsiveness. Previous results have revealed a role for prolyl hydroxylation and resultant von Hippel-Lindau protein (pVHL) interactions in the ubiquitin-proteasome-mediated degradation of HIF-1alpha. However, neither inhibition of prolyl hydroxylases nor mutation of HIF-1alpha-hydroxylated prolines involved with pVHL-mediated binding inhibits the observed FOXO4-mediated down-regulation of HIF-1alpha. These results suggest a novel alternate mechanism for hypoxic regulation that is dependent upon the level of activation of FOXO4-mediated transcription.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据