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

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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Hypoxia-Inducible Factor 1
Protein Stability
Down-Regulation
Ubiquitination
Hydroxylation
Acetylation
Vascular Endothelial Growth Factor A
Up-Regulation
Histone Deacetylase 1
Proteins
Mutant Proteins
Breast Neoplasms
Tumors
Genes
Degradation

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

HEXIM1 down-regulates hypoxia-inducible factor-1α protein stability. / Yeh, I. Ju; Ogba, Ndiya; Bensigner, Heather; Welford, Scott; Montano, Monica M.

In: Biochemical Journal, Vol. 456, No. 2, 01.12.2013, p. 195-204.

Research output: Contribution to journalArticle

Yeh, I. Ju ; Ogba, Ndiya ; Bensigner, Heather ; Welford, Scott ; Montano, Monica M. / HEXIM1 down-regulates hypoxia-inducible factor-1α protein stability. In: Biochemical Journal. 2013 ; Vol. 456, No. 2. pp. 195-204.
@article{207ed45d701b4185bd746417a1d5b0a0,
title = "HEXIM1 down-regulates hypoxia-inducible factor-1α protein stability",
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.",
keywords = "Breast cancer, Hexamethylene-bis-acetamide-inducible protein-1 (HEXIM1), Histone deacetylase (HDAC), Hypoxia-inducible factor 1α (HIF-1α), Prolyl hydroxylase (PHD)",
author = "Yeh, {I. Ju} and Ndiya Ogba and Heather Bensigner and Scott Welford and Montano, {Monica M.}",
year = "2013",
month = "12",
day = "1",
doi = "10.1042/BJ20130592",
language = "English (US)",
volume = "456",
pages = "195--204",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "2",

}

TY - JOUR

T1 - HEXIM1 down-regulates hypoxia-inducible factor-1α protein stability

AU - Yeh, I. Ju

AU - Ogba, Ndiya

AU - Bensigner, Heather

AU - Welford, Scott

AU - Montano, Monica M.

PY - 2013/12/1

Y1 - 2013/12/1

N2 - 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.

AB - 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.

KW - Breast cancer

KW - Hexamethylene-bis-acetamide-inducible protein-1 (HEXIM1)

KW - Histone deacetylase (HDAC)

KW - Hypoxia-inducible factor 1α (HIF-1α)

KW - Prolyl hydroxylase (PHD)

UR - http://www.scopus.com/inward/record.url?scp=84887432218&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887432218&partnerID=8YFLogxK

U2 - 10.1042/BJ20130592

DO - 10.1042/BJ20130592

M3 - Article

C2 - 24015760

AN - SCOPUS:84887432218

VL - 456

SP - 195

EP - 204

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 2

ER -