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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-1α

Brian J. Murphy, Tomoki Kimura, Barbara G. Sato, Yihui Shi and Glen K. Andrews
Brian J. Murphy
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Tomoki Kimura
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Barbara G. Sato
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Yihui Shi
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Glen K. Andrews
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DOI: 10.1158/1541-7786.MCR-07-0341 Published March 2008
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Abstract

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-1α (HIF-1α) is essential for induction of MT-1 by hypoxia, but not zinc. Chromatin immunoprecipitation assays revealed that MTF-1 and HIF-1α are both recruited to the mouse MT-I promoter in response to hypoxia, but not zinc. In the absence of HIF-1α, MTF-1 is recruited to the MT-I promoter but fails to activate MT-I gene expression in response to hypoxia. Thus, HIF-1α 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-1α, 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)

Keywords:
  • metal transcription factor-1
  • hypoxia-inducible factor-1α
  • hypoxia
  • transcriptional complex
  • Mechanisms of transcription

Footnotes

  • ↵4 Y. Li et al., in preparation.

  • ↵5 B. Sato and B. Murphy, unpublished results.

  • Grant support: NIH grants CA057692 (B.J. Murphy) and ES05704 (G.K. Andrews).

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

    • Accepted November 14, 2007.
    • Received July 20, 2007.
    • Revision received October 26, 2007.
  • American Association for Cancer Research
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Molecular Cancer Research: 6 (3)
March 2008
Volume 6, Issue 3
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Metallothionein Induction by Hypoxia Involves Cooperative Interactions between Metal-Responsive Transcription Factor-1 and Hypoxia-Inducible Transcription Factor-1α
Brian J. Murphy, Tomoki Kimura, Barbara G. Sato, Yihui Shi and Glen K. Andrews
Mol Cancer Res March 1 2008 (6) (3) 483-490; DOI: 10.1158/1541-7786.MCR-07-0341

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Metallothionein Induction by Hypoxia Involves Cooperative Interactions between Metal-Responsive Transcription Factor-1 and Hypoxia-Inducible Transcription Factor-1α
Brian J. Murphy, Tomoki Kimura, Barbara G. Sato, Yihui Shi and Glen K. Andrews
Mol Cancer Res March 1 2008 (6) (3) 483-490; DOI: 10.1158/1541-7786.MCR-07-0341
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