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Signaling and Regulation

Metallothionein Induction by Hypoxia Involves Cooperative Interactions between Metal-Responsive Transcription Factor-1 and Hypoxia-Inducible Transcription Factor-1

¹ Biosciences Division, SRI International, Menlo Park, California; ² Department of Toxicology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan; and ³ Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas

Requests for reprints: Brian J. Murphy, Biosciences, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025. Phone: 650-859-4213. E-mail: brian.murphy{at}sri.com

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 (HIF-1) is essential for induction of MT-1 by hypoxia, but not zinc. Chromatin immunoprecipitation assays revealed that MTF-1 and HIF-1 are both recruited to the mouse MT-I promoter in response to hypoxia, but not zinc. In the absence of HIF-1, MTF-1 is recruited to the MT-I promoter but fails to activate MT-I gene expression in response to hypoxia. Thus, HIF-1 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, 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. (Mol Cancer Res 2008;6(3):483–90)