Metallothionein induction by hypoxia involves cooperative interactions between metal-responsive transcription factor-1 and hypoxia-inducible transcription factor-1alpha.
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-1alpha (HIF-1alpha) is essential for induction of MT-1 by hypoxia, but not zinc. Chromatin immunoprecipitation assays revealed that MTF-1 and HIF-1alpha are both recruited to the mouse MT-I promoter in response to hypoxia, but not zinc. In the absence of HIF-1alpha, MTF-1 is recruited to the MT-I promoter but fails to activate MT-I gene expression in response to hypoxia. Thus, HIF-1alpha 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-1alpha, 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.
Murphy
Brian J
BJ
Biosciences Division, SRI International, Menlo Park, CA 94025, USA. brian.murphy@sri.com
Kimura
Tomoki
T
Sato
Barbara G
BG
Shi
Yihui
Y
Andrews
Glen K
GK
D016475:3T3 Cells; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000502:physiology*; D017353:Gene Deletion; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008668:Metallothionein / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D034622:RNA Interference; D014157:Transcription Factors / Q000502:physiology*; D015032:Zinc / Q000494:pharmacology; D000097809:Transcription Factor MTF-1
D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008668:Metallothionein; D014157:Transcription Factors; D015032:Zinc; D000097809:Transcription Factor MTF-1; C497443:Hif1a protein, mouse