Yeh IJ, Ogba N, Bensigner H, Welford SM, Montano MM

We have previously reported on the inhibition of Hypoxia Inducible Factor alpha (HIF-1α) regulated pathways by Hexamethylene-bis-acetamide-inducible (HMBA) protein 1 (HEXIM1). Disruption of HEXIM1 activity in a knock-in mouse model expressing a mutant HEXIM1 protein resulted in increased susceptibility to the development of mammary tumors, partly by upregulation of vascular ...

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endothelial growth factor (VEGF) expression, HIF-1α expression, and aberrant vascularization. We now report on the mechanistic basis for HEXIM1 regulation of HIF-1α. We observed direct interaction between HIF-1α and HEXIM1 and HEXIM1 upregulated hydroxylation of HIF-1α, resulting in the induction of the interaction of HIF-1α with von Hippel-Lindau protein (pVHL) and ubiquitination of HIF-1α. The upregulation of hydroxylation involves HEXIM1 mediated induction of prolyl hydroxylase 3 (PHD3) expression and interaction of PHD3 with HIF-1α. Acetylation of HIF-1α has been proposed to result in increased interaction of HIF-1α with pVHL and induced pVHL-mediated ubiquitination, which leads to the proteasomal degradation of HIF-1α. HEXIM1 also attenuated the interaction of HIF-1α with histone deacetylase 1 (HDAC1), resulting in acetylation of HIF-1α. The consequence of HEXIM1 downregulation of HIF-1α protein expression is attenuated expression of HIF-1α target genes in addition to VEGF and inhibition of HIF-1α regulated cell invasion.

Date: Sep. 10, 2013

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