Genetic instability: the dark side of the hypoxic response.

Abstract

Under low oxygen tension, the activated transcription factor HIF-1alpha upregulates an array of hypoxia-inducible genes via heterodimerization with ARNT and binding to the hypoxia-responsive element in the promoter. Alternatively, HIF-1alpha regulates hypoxia-responsive genes by functionally antagonizing the oncoprotein Myc via protein-protein interactions. This so-called HIF-1alpha-Myc mechanism apparently not only accounts for the gene upregulation, but also for the gene downregulation during hypoxia, depending upon the activating and repressive nature of Myc in gene expression. Indeed, our recent study demonstrated that both mismatch repair genes, MSH2 and MSH6, are inhibited by this mechanism in a p53-dependent manner. In particular, the constitutively bound transcription factor Sp1 serves as a molecular switch by recruiting HIF-1alpha in hypoxia to displace the transcription activator Myc from the promoter. Therefore, our findings shed light on the mechanisms underlying hypoxia-induced genetic instability, an "adverse"effect of the hypoxic response, and yet a germane process to tumor survival and progression.

• Authors: Kenneth K W To, Minori Koshiji, Stefanie Hammer, L Eric Huang
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 4 Issue 7 Pg. 881-2 (Jul 2005) ISSN: 1551-4005 [Electronic] United States
• PMID: 15970707 (Publication Type: Journal Article)

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• MSH2 protein, human
• MutS Homolog 2 Protein

Topics

• Cell Hypoxia (genetics)
• Colonic Neoplasms (metabolism)
• Genomic Instability (genetics)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• MutS Homolog 2 Protein (metabolism)