Regulation der Stabilität des Hypoxie-induzierbaren Faktors durch Glycogen-Synthase-Kinase-3 (English shop)

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The long-term adaptation of a cell to changes in O2 supply occurs through modulation of gene expression. The transcriptional control of gene expression is exerted via the function of various transcription factors. Under hypoxia, hypoxia-inducible factor-1 (HIF-1) plays a decisive role in the transcriptional activation of the expression of many genes, such as erythropoietin (EPO), plasminogen activator inhibitor-1 (PAI-1) and vascular endothelial growth factor (VEGF). HIF-1 consists of an O2-sensitive subunit, HIF-1α, and a constitutively expressed subunit, HIF-1ß, also known as aryl hydrocarbon receptor nuclear translocator protein (ARNT). The O2-dependent regulation of HIF-1α occurs predominantly through post-translational modification. Under normoxia, two proline residues (P402/P564) within the O2-dependent degradation domain (ODD) and one asparagine residue (N803) in the C-terminal transactivation domain (C-TAD) are hydroxylated in an oxygen-dependent manner. Proline hydroxylation then mediates the binding of the von Hippel-Lindau tumour suppressor protein (VHL), ubiquitinylation and proteasomal degradation of HIF-1α. Asparagine hydroxylation prevents the recruitment of the coactivator p300. In addition to the O2-dependent regulation of HIF-1α, many growth factors and hormones, including insulin acting via the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB) signalling pathway, can induce HIF-1α levels independently of O2. The increase in HIF-1α protein levels is not directly attributable to phosphorylation by PKB, but is probably caused by further PKB substrates such as mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3). GSK-3 in particular could play a role in the regulation of HIF-1α protein stability, since potential consensus sequences for GSK-3 appear to exist in the O2-dependent degradation domain (ODD) of HIF-1α.