The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF).
The hypoxia inducible factor (HIF) plays an important role in the progression of a number of pathophysiological processes including tumorigenesis. In addition to several well characterized oxygen-dependent modes of regulation, the function of the HIF transcription factor can also be influenced through the action of other regulatory pathways. Misregulation of these factors resulting in inappropriate HIF expression or activity can contribute to the progression of human cancers through the induction of genes promoting angiogenesis, glycolysis, cell survival, and metastasis, among other processes. The candidate tumor suppressor protein inhibitor of growth family member 4 (ING4) has recently been implicated as a repressor of angiogenesis and tumor growth through association with NF-kappaB. Here we demonstrate that suppression of ING4 further induces HIF transcriptional activity as well. ING4 directly associates with the HIF prolyl hydroxylase, an Fe(II)-dependent oxygenase previously shown to mediate HIF stability as a function of oxygen availability. However, rather than affecting HIF's stability, ING4 mediates HIF's activity. These data support a model in which, in addition to regulating HIF stability, HIF prolyl hydroxylases can modulate HIF function through the recruitment of ING4, a likely component of a chromatin-remodeling complex.
Ozer
Abdullah
A
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA.
Wu
Leeju C
LC
Bruick
Richard K
RK
D015153:Blotting, Western; D018797:Cell Cycle Proteins; D002458:Cell Fractionation; D047369:Chromatin Immunoprecipitation; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004926:Escherichia coli; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D005982:Glutathione Transferase; D006367:HeLa Cells; D018398:Homeodomain Proteins; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047468:Immunoprecipitation; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism*; D034622:RNA Interference; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D018398:Homeodomain Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C483230:ING4 protein, human; D016328:NF-kappa B; D009687:Nuclear Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D011393:Procollagen-Proline Dioxygenase; D005982:Glutathione Transferase; D010100:Oxygen