NDLI: The phosphorylation status of PAS-B distinguishes HIF-1α from HIF-2α in NBS1 repression

Content Provider	PubMed Central
Author	To, Kenneth K. -w Sedelnikova, Olga A. Samons, Melissa Bonner, William M. Huang, L. Eric
Copyright Year	2006
Abstract	Hypoxia promotes genetic instability for tumor progression. Recent evidence indicates that the transcription factor HIF-1α impairs DNA mismatch repair, yet the role of HIF-1α isoform, HIF-2α, in tumor progression remains obscure. In pursuit of the involvement of HIF-α in chromosomal instability, we report here that HIF-1α, 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-2α fails to do so. We demonstrate that this functional distinction stems from phosphorylation of HIF-2α 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-1α from HIF-2α, and arguing a unique role for HIF-1α in tumor progression by promoting genomic instability.
Related Links	http://dx.doi.org/10.1038/sj.emboj.7601369
Ending Page	4794
Page Count	11
Starting Page	4784
File Format	PDF
ISSN	02614189
e-ISSN	14602075
Journal	The EMBO Journal
Issue Number	20
Volume Number	25
Language	English
Publisher Date	2006-10-18
Access Restriction	Open
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Immunology and Microbiology(all) Neuroscience(all) Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology and Microbiology Medicine Molecular Biology

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