Human HIF-3alpha4 is a dominant-negative regulator of HIF-1 and is down-regulated in renal cell carcinoma.
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-1alpha, signifying a critical role of the HIF pathway in cancer development. ... The recently identified third member of the human HIF-alpha family, HIF-3alpha, produces multiple splice variants that contain extra DNA binding elements and protein-protein interaction motifs not found in HIF-1alpha or HIF-2alpha. Here we report the molecular cloning of the alternatively spliced human HIF-3alpha variant HIF-3alpha4 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-3alpha4 suppresses the transcriptional activity of HIF-1 and siRNA-mediated knockdown of the endogenous HIF-3alpha4 increases transcription by hypoxia-inducible genes. HIF-3alpha4 itself is oxygen-regulated, suggesting a novel feedback mechanism of controlling HIF-1 activity. Furthermore, the expression of HIF-3alpha4 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-3alpha4 in vivo and underscore its potential significance in renal epithelial oncogenesis.
Mesh Terms:
Amino Acid Sequence, Aryl Hydrocarbon Receptor Nuclear Translocator, Base Sequence, Basic Helix-Loop-Helix Transcription Factors, Carcinoma, Renal Cell, Cell Line, Tumor, Cloning, Molecular, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney Neoplasms, Molecular Sequence Data, RNA, Small Interfering, Response Elements, Transcription Factors, Transcription, Genetic
Amino Acid Sequence, Aryl Hydrocarbon Receptor Nuclear Translocator, Base Sequence, Basic Helix-Loop-Helix Transcription Factors, Carcinoma, Renal Cell, Cell Line, Tumor, Cloning, Molecular, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney Neoplasms, Molecular Sequence Data, RNA, Small Interfering, Response Elements, Transcription Factors, Transcription, Genetic
FASEB J.
Date: Sep. 01, 2005
PubMed ID: 16126907
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