Oxygen-independent Regulation of HIF-1: Novel Involvement of PI3K/AKT/mTOR Pathway in Cancer

被引:220
作者
Agani, Faton [1 ]
Jiang, Bing-Hua [1 ]
机构
[1] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA
关键词
AKT; growth factors; HIF-1; hypoxia; MAPK; oncogenes; PI3K; tumor suppressors; HYPOXIA-INDUCIBLE FACTOR; ENDOTHELIAL GROWTH-FACTOR; MITOCHONDRIAL RESPIRATORY-CHAIN; PHOSPHATIDYLINOSITOL; 3-KINASE; FACTOR; 1-ALPHA; FACTOR-I; TRANSCRIPTIONAL ACTIVITY; HIF-1-ALPHA EXPRESSION; NORMOXIC CONDITIONS; SIGNALING PATHWAYS;
D O I
10.2174/1568009611313030003
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Studies on erythropoietin regulation led to discovery of hypoxia-inducible factor 1 (HIF-1), a transcription factor which is central component of oxygen sensing mechanism in mammalian cells. The number of HIF-1 and hypoxia-regulated target genes has grown exponentially and includes genes that encode proteins with roles in erythropoiesis, angiogenesis, glycolytic pathway, glucose transport, metastasis, and cell survival. Thus, HIF-1 claimed the role of the master that orchestrates cellular responses to oxygen deprivation. In addition, HIF-1 is also activated or influenced through oxygen-independent mechanisms via growth factors, deregulated oncogenes, and/or tumor suppressors. Whereas HIF prolyl hydroxylases (PHDs) regulate HIF-1 (and subsequently identified HIF-2) during hypoxia, the PI3K, AKT and MAPK pathways mediate primarily non-hypoxic HIF regulation. Here we will focus primarily on pathways that lead to HIF activation via PI3K/AKT, and mTOR/p70S6K1. In addition, recent studies have revealed novel factors and mechanisms that regulate oxygen-independent HIF-1 alpha and HIF-2 alpha degradation. HIFs play important roles in many processes in health and disease. Consequently, HIFs and pathways (PI3K/AKT and mTOR/p70S6K1) that lead to normoxic HIF activation are considered potential therapeutic targets in these pathologies.
引用
收藏
页码:245 / 251
页数:7
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