tailieunhanh - Báo cáo khoa học: The subtle side to hypoxia inducible factor (HIFa) regulation

The transcription factor hypoxia inducible factora-subunit (HIFa)is pivotal in the cellular response to the stress of hypoxia. Post-translational modification of HIFa by hydroxylase enzymes has recently been identified as a key oxygen sensing mechanism within the cell. The absence of the substrate oxygen prevents the hydroxylases from modi-fying HIFaduring hypoxia and allows dramatic up-regula-tion of both HIFaprotein stability and transcriptional activation capability. | Eur. J. Biochem. 270 791-798 2003 FEBS 2003 doi REVIEW ARTICLE The subtle side to hypoxia inducible factor HIFa regulation Rebecca L. Bilton and Grant W. Booker Department of Molecular Biosciences The University of Adelaide Australia The transcription factor hypoxia inducible factor a-subunit HIFa is piootal in the eellular eespnn to I lie ttesss of hypoxia. Post-translational modification of HIFa by hydroxylase enzymes has recently been identified as a key oxygen sensing mechanism within the cell. The absence of the substrate oxygen prevents the hydroxylases from modifying HIFa during hypoxia and allows dramatic up-regulation of both HIFa protein stability and transcriptional activation capability. In addition to this oxygen-dependent response increased HIFa protein levels and or enhanced transcriptional activity during normoxic conditions can be stimulated by various receptor-mediated factors such as growth-factors and cytokines insulin insulin-like growth factor 1 or 2 endothelial growth factor tumour necrosis factor a angiotensin-2 . Oncogenes are also capable of HIFa activation. This induction is generally less intense than that stimulated by hypoxia and although not fully elucidated appears to occur via hypoxia-independent receptor-mediated signal pathways involving either phosphatidyl -inositol-3-kinase Akt or mitogen activated protein kinase MAPK pathways depending on the cefi-ypee. Aciivniion of Akt increases HIFa protein synthesis in the cell and results in increased HIFa protein and transcriptional activity. MAPK also activates HIFa protein synthesis and additionally may potentiate HIF1a transcriptional activity via a separate mechanism that does not necessarily require protein stabilization. Here we review the mechanisms and function of receptor-mediated signals in the multifaceted regulation ofHIFa. Keywords HIFa growth factor oncogene PI3K MAPK. Introduction Spurred-on by the discovery of their involvement in the .