Journal
MOLECULAR CANCER RESEARCH
Volume 6, Issue 3, Pages 483-490Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-07-0341
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Funding
- NCI NIH HHS [CA057692] Funding Source: Medline
- NIEHS NIH HHS [ES05704] Funding Source: Medline
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Mammalian metallothionein (MT) genes are transcriptionally activated by the essential metal zinc as well as by environmental stresses, including toxic metal overload and redox fluctuations. In addition to playing a key role in zinc homeostasis, MT proteins can protect against metal- and oxidant-induced cellular damage, and may participate in other fundamental physiologic and pathologic processes such as cell survival, proliferation, and neoplasia. Previously, our group reported a requirement for metal-responsive transcription factor-1 (MTF-1) in hypoxia-induced transcription of mouse MT-I and human MT-IIA genes. Here, we provide evidence that the protumorigenic hypoxia-inducible transcription factor-1 alpha (HIF-1 alpha) is essential for induction of MT-1 by hypoxia, but not zinc. Chromatin immunoprecipitation assays revealed that MTF-1 and HIF-1 alpha are both recruited to the mouse MT-I promoter in response to hypoxia, but not zinc. In the absence of HIF-1 alpha, MTF-1 is recruited to the MT-I promoter but fails to activate MT-I gene expression in response to hypoxia. Thus, HIF-1 alpha seems to function as a coactivator of MT-I gene transcription by interacting with MTF-1 during hypoxia. Coimmunoprecipitation studies suggest interaction between MTF-1 and HIF-1 alpha, either directly or as mediated by other factors. It is proposed that association of these important transcription factors in a multiprotein complex represents a common strategy to control unique sets of hypoxia-inducible genes in both normal and diseased tissue.
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