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-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.
Highlights
The cysteine-rich metallothioneins (MT) bind metals, including zinc, copper, and cadmium, with high affinity andThe metal-responsive transcription factor-1 (MTF-1) is a central regulator of metal-inducible expression of MT-I and MT-II
MT-I transcription is increased during hypoxia in a MTF-1 – dependent manner; increases in MT-1 mRNA levels occur within 4 hours after exposure, and maximum induction occurs within 8 to 12 hours [43, 64]
MTF-1 is required in the hypoxia accumulation of HIF-1a, a central transcriptional regulator of the cellular response to hypoxia [57]
Summary
The metal-responsive transcription factor-1 (MTF-1) is a central regulator of metal-inducible expression of MT-I and MT-II. Current models of MTF-1 activation suggest that zinc directly and reversibly modulates highly specific, linkermediated zinc finger interactions in MTF-1, resulting in translocation of this transcription factor to the nucleus and rate-limiting binding to metal response elements [MRE; TGC(G/C)CNC(G)] within proximal MT promoters [29,30,31,32,33,34]. Collaborators, suggest that MTF-1 can contribute to tumorigenic processes, in part, through its transcriptional action as either a positive or a negative regulator of numerous genes, including zinc transporter 1 (ZnT1), PIGF, transforming growth factor-b1 (TGF-b1), tissue transglutaminase-2 (TG2), and Zip10 [20, 46,47,48,49]. A limited number of these studies have focused on the chromatin-packaged MT-I promoter, and those only in the context of activation by metal
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