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PNAS 102 (21): 7481-7486

Copyright © 2005 by the National Academy of Sciences.

BIOCHEMISTRY

The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF)

Abdullah Ozer, Leeju C. Wu, and Richard K. Bruick *

Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038

Communicated by Steven L. McKnight, University of Texas Southwestern Medical Center, Dallas, TX, April 1, 2005

Received for publication January 31, 2005.

Abstract: 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-{kappa}B. 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.

Key Words: prolyl hydroxylase • inhibitor of growth

Abbreviations: HIF, hypoxia inducible factor; VHL, von Hippel–Lindau tumor suppressor gene; HPH, HIF prolyl hydroxylase; FIH-1, factor inhibiting HIF-1; ING, inhibitor of growth family member; PHD, plant homeodomain; siRNA, short interfering RNA.

* To whom correspondence should be addressed. E-mail: bruick{at}biochem.swmed.edu.

© 2005 by The National Academy of Sciences of the USA

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