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Abstract:
Under low oxygen tension, the activated transcription factor HIF-1? upregulates an array of hypoxia-inducible genes via heterodimerization with ARNT and binding to the hypoxia-responsive element in the promoter. Alternatively, HIF-1? regulates hypoxia-responsive genes by functionally antagonizing the oncoprotein Myc via protein-protein interactions. This so-called HIF-1?–Myc mechanism apparently not only accounts for the gene up-regulation, but also for the gene down-regulation during hypoxia, depending upon the active 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-1? 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.
