HEXIM1 down-regulates hypoxia-inducible factor-1α protein stability

I. Ju Yeh, Ndiya Ogba, Heather Bensigner, Scott M. Welford, Monica M. Montano

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

We have previously reported on the inhibition of HIF-1α (hypoxia-inducible factor α)-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-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 up-regulated hydroxylation of HIF-1α, resulting in the induction of the interaction of HIF-1α with pVHL(von Hippel-Lindau protein) and ubiquitination of HIF-1α. The up-regulation of hydroxylation involves HEXIM1-mediated induction of PHD3 (prolyl hydroxylase 3) expression and interaction of PHD3with 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 HDAC1 (histone deacetylase 1), resulting in acetylation of HIF-1α. The consequence of HEXIM1 down-regulation 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.

Original languageEnglish (US)
Pages (from-to)195-204
Number of pages10
JournalBiochemical Journal
Volume456
Issue number2
DOIs
StatePublished - Dec 1 2013

    Fingerprint

Keywords

  • Breast cancer
  • Hexamethylene-bis-acetamide-inducible protein-1 (HEXIM1)
  • Histone deacetylase (HDAC)
  • Hypoxia-inducible factor 1α (HIF-1α)
  • Prolyl hydroxylase (PHD)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this