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PMID: 17024177 Published · ppublish English Journal Article Research Support, N.I.H., Intramural

The phosphorylation status of PAS-B distinguishes HIF-1alpha from HIF-2alpha in NBS1 repression.

The EMBO journal ·Vol. 25 ·No. 20 ·2006-10-18 ·Pages 4784-94

To KK, Sedelnikova OA, Samons M, Bonner WM, Huang LE

Abstract

Hypoxia promotes genetic instability for tumor progression. Recent evidence indicates that the transcription factor HIF-1alpha impairs DNA mismatch repair, yet the role of HIF-1alpha isoform, HIF-2alpha, in tumor progression remains obscure. In pursuit of the involvement of HIF-alpha in chromosomal instability, we report here that HIF-1alpha, specifically its PAS-B, induces DNA double-strand breaks at least in part by repressing the expression of NBS1, a crucial DNA repair gene constituting the MRE11A-RAD50-NBS1 complex. Despite strong similarities between the two isoforms, HIF-2alpha fails to do so. We demonstrate that this functional distinction stems from phosphorylation of HIF-2alpha Thr-324 by protein kinase D1, which discriminates between subtle differences of the two PAS-B in amino-acid sequence, thereby precluding NBS1 repression. Hence, our findings delineate a molecular pathway that functionally distinguishes HIF-1alpha from HIF-2alpha, and arguing a unique role for HIF-1alpha in tumor progression by promoting genomic instability.

MeSH Terms
Animals Basic Helix-Loop-Helix Transcription Factors/genetics,metabolism Cell Cycle Proteins/genetics,metabolism Cell Line Chromosomal Instability/genetics DNA Repair/genetics Down-Regulation/genetics Gene Expression Regulation, Neoplastic/genetics Humans Hypoxia-Inducible Factor 1, alpha Subunit/genetics,metabolism Multiprotein Complexes/genetics,metabolism Neoplasm Proteins/genetics,metabolism Neoplasms/genetics,metabolism Nuclear Proteins/genetics,metabolism Phosphorylation Protein Processing, Post-Translational Protein Structure, Tertiary/genetics Rabbits
Chemicals
Basic Helix-Loop-Helix Transcription Factors Cell Cycle Proteins HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit Multiprotein Complexes NBN protein, human Neoplasm Proteins Nuclear Proteins endothelial PAS domain-containing protein 1
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
To Kenneth K-W
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sedelnikova Olga A
Samons Melissa
Bonner William M
Huang L Eric
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7601369
Published
2006-10-18
Epub
2006-00-05
Pages
4784-94
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1618093
Subset
IM
Grants
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1038/sj.emboj.7601369 PMC Full Text View journal details
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