| First Author | Yeh IJ | Year | 2013 |
| Journal | Biochem J | Volume | 456 |
| Issue | 2 | Pages | 195-204 |
| PubMed ID | 24015760 | Mgi Jnum | J:203807 |
| Mgi Id | MGI:5528766 | Doi | 10.1042/BJ20130592 |
| Citation | Yeh IJ, et al. (2013) HEXIM1 down-regulates hypoxia-inducible factor-1alpha protein stability. Biochem J 456(2):195-204 |
| abstractText | We have previously reported on the inhibition of HIF-1alpha (hypoxia-inducible factor alpha)-regulated pathways by HEXIM1 [HMBA (hexamethylene-bis-acetamide)-inducible protein 1]. Disruption of HEXIM1 activity in a knock-in mouse model expressing a mutant HEXIM1 protein resulted in increased susceptibility to the development of mammary tumours, partly by up-regulation of VEGF (vascular endothelial growth factor) expression, HIF-1alpha expression and aberrant vascularization. We now report on the mechanistic basis for HEXIM1 regulation of HIF-1alpha. We observed direct interaction between HIF-1alpha and HEXIM1, and HEXIM1 up-regulated hydroxylation of HIF-1alpha, resulting in the induction of the interaction of HIF-1alpha with pVHL (von Hippel-Lindau protein) and ubiquitination of HIF-1alpha. The up-regulation of hydroxylation involves HEXIM1-mediated induction of PHD3 (prolyl hydroxylase 3) expression and interaction of PHD3 with HIF-1alpha. Acetylation of HIF-1alpha has been proposed to result in increased interaction of HIF-1alpha with pVHL and induced pVHL-mediated ubiquitination, which leads to the proteasomal degradation of HIF-1alpha. HEXIM1 also attenuated the interaction of HIF-1alpha with HDAC1 (histone deacetylase 1), resulting in acetylation of HIF-1alpha. The consequence of HEXIM1 down-regulation of HIF-1alpha protein expression is attenuated expression of HIF-1alpha target genes in addition to VEGF and inhibition of HIF-1alpha-regulated cell invasion. |
