Tumor Suppressor Controls HIF Activity

Abstract

When the oxygen supply gets low, mammalian cells initiate an adaptive program involving a transcription factor called hypoxia-inducible factor (HIF). The expression of HIF and its target genes increases under hypoxic conditions, allowing the cell to survive oxidative stress. Under normal oxygen conditions, the transcription factor is modified on proline residues by HIF prolyl hydroxylases (HPHs). Hydroxylation allows interaction with a tumor suppressor factor called von Hippel-Lindau (VHL), and the complex becomes a target for proteosomal degradation. Ozer et al. have identified a tumor suppressor that controls HIF activity rather than HIF abundance. When expression of the tumor suppressor protein inhibitor of growth factor 4 (ING4) was blocked by RNA interference in cultured mammalian cells, the effect of hypoxia on HIF activity was enhanced--expression of HIF target genes increased. Although direct interaction between HIF and ING4 was not detected, yeast two-hybrid analysis identified ING4 interaction with the hydroxylase HPH-2. Endogenous ING4 and HPH-2 were found in the nuclear fraction of cell lysates. However, ING4 was not a substrate for hydroxylation by HPH-2. ING4 also did not affect HPH-2 activity on HIF. Because ING family members interact with chromatin-remodeling complexes that promote or suppress transcription, the authors suggest that ING4 that associates with HPH-2 gets recruited to HIF, where it subsequently acts as an adapter to recruit transcriptional repressors that control HIF activity. A. Ozer, L. C. Wu, R. K. Bruick, The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). Proc. Natl. Acad. Sci. U.S.A. 102 , 7481-7486 (2005). [Abstract] [Full Text]