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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.
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页码:245 / 251
页数:7
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