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4 is a dominant-negative regulator of HIF-1 and is down-regulated in renal cell carcinoma
* Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada;
Department of Pathology, University Health Network, Princess Margaret Hospital, Toronto, Ontario, Canada;
Department of Public Health and Molecular Toxicology, School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, Japan; and
Departments of Urology and Surgical Oncology, University of Toronto and Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada
1Correspondence: Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, Ontario, M5S 1A8, Canada. E-mail: michael.ohh{at}utoronto.ca
A universal response to changes in cellular oxygen tension is governed by a family of heterodimeric transcription factors called hypoxia-inducible factor (HIF). Tumor hypoxia, as well as various cancer-causing mutations, has been shown to elevate the level of HIF-1
, signifying a critical role of the HIF pathway in cancer development. The recently identified third member of the human HIF- family, HIF-3, produces multiple splice variants that contain extra DNA binding elements and protein-protein interaction motifs not found in HIF-1 or HIF-2. Here we report the molecular cloning of the alternatively spliced human HIF-3 variant HIF-34 and show that it attenuates the ability of HIF-1 to bind hypoxia-responsive elements located within the enhancer/promoter of HIF target genes. The overexpression of HIF-34 suppresses the transcriptional activity of HIF-1 and siRNA-mediated knockdown of the endogenous HIF-34 increases transcription by hypoxia-inducible genes. HIF-34 itself is oxygen-regulated, suggesting a novel feedback mechanism of controlling HIF-1 activity. Furthermore, the expression of HIF-34 is dramatically down-regulated in the majority of primary renal carcinomas. These results demonstrate an important dominant-negative regulation of HIF-1-mediated gene transcription by HIF-34 in vivo and underscore its potential significance in renal epithelial oncogenesis.— Maynard, M. A., Evans, A. J., Hosomi, T., Hara, S., Jewett, M. A. S., Ohh, M. Human HIF-34 is a dominant-negative regulator of HIF-1 and is down-regulated in renal cell carcinoma.
Key Words: HIF-34 • VHL • RCC • hypoxia
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