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 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 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.
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Research Article|
November 08 2013
HEXIM1 down-regulates hypoxia-inducible factor-1α protein stability
I-Ju Yeh;
I-Ju Yeh
*Department of Pharmacology, Division of General Medical Science and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, U.S.A.
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Ndiya Ogba;
Ndiya Ogba
*Department of Pharmacology, Division of General Medical Science and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, U.S.A.
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Heather Bensigner;
Heather Bensigner
*Department of Pharmacology, Division of General Medical Science and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, U.S.A.
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Scott M. Welford;
Scott M. Welford
†Department of Radiation Oncology, Division of General Medical Science and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, U.S.A.
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Monica M. Montano
Monica M. Montano
1
*Department of Pharmacology, Division of General Medical Science and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, U.S.A.
1To whom correspondence should be addressed (email mxm126@case.edu).
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Publisher: Portland Press Ltd
Received:
April 26 2013
Revision Received:
August 23 2013
Accepted:
September 10 2013
Accepted Manuscript online:
September 10 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 456 (2): 195–204.
Article history
Received:
April 26 2013
Revision Received:
August 23 2013
Accepted:
September 10 2013
Accepted Manuscript online:
September 10 2013
Citation
I-Ju Yeh, Ndiya Ogba, Heather Bensigner, Scott M. Welford, Monica M. Montano; HEXIM1 down-regulates hypoxia-inducible factor-1α protein stability. Biochem J 1 December 2013; 456 (2): 195–204. doi: https://doi.org/10.1042/BJ20130592
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