Human HIF-3[alpha]4 is a dominant-negative regulator of HIF-1 and is down-regulated in renal cell carcinoma

• Published in: The FASEB journal 2005, Vol.19 (11), p.1396-1406
• Main Authors: Maynard, Mindy A, Evans, Andrew J, Hosomi, Tomoko, Hara, Shuntaro, Jewett, Michael A. S, Ohh, Michael
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860

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[alpha], signifying a critical role of the HIF pathway in cancer development. The recently identified third member of the human HIF-[alpha] family, HIF-3[alpha], produces multiple splice variants that contain extra DNA binding elements and protein-protein interaction motifs not found in HIF-1[alpha] or HIF-2[alpha]. Here we report the molecular cloning of the alternatively spliced human HIF-3[alpha] variant HIF-3[alpha]4 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-3[alpha]4 suppresses the transcriptional activity of HIF-1 and siRNA-mediated knockdown of the endogenous HIF-3[alpha]4 increases transcription by hypoxia-inducible genes. HIF-3[alpha]4 itself is oxygen-regulated, suggesting a novel feedback mechanism of controlling HIF-1 activity. Furthermore, the expression of HIF-3[alpha]4 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-3[alpha]4 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-3[alpha]4 is a dominant-negative regulator of HIF-1 and is down-regulated in renal cell carcinoma.