The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity.

Zaibo Li, Dakun Wang, Xi Na, Susan R Schoen, Edward M Messing, Guan Wu

Departments of Urology and Pathology, and The James PWilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.

The EMBO journal 2003 Apr 15

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The von Hippel-Lindau tumor suppressor (pVHL) is a component of an E3 ubiquitin ligase and targets hypoxia-inducible factor-1alpha (HIF-1alpha) for ubiquitylation and degradation under normoxic conditions. pVHL also directly inhibits HIF-1alpha transactivation by recruiting histone deacetylases. Here, we report a novel pVHL-interacting protein that functions as a negative regulator of HIF-1alpha transactivation. This protein, generated from the ZnF197 locus by alternative splicing, contains a Kruppel-associated box (KRAB)-A domain and a SCAN domain, but lacks the 22 C2H2-type zinc fingers present in ZnF197. Therefore, we named this protein pVHL-associated KRAB-A domain-containing protein (VHLaK). We demonstrate that the KRAB-A domain in VHLaK mediates pVHL binding and functions as a transcriptional repression module. The SCAN domain mediates VHLaK homo-oligomerization, which enhances VHLaK repressive activity. pVHL can recruit VHLaK to repress HIF-1alpha transcriptional activity and HIF-1alpha-induced VEGF expression. Finally, we demonstrate that pVHL, VHLaK and KAP1/TIF-1beta can be recruited into a single complex, indicating that KAP1/TIF-1beta may participate in pVHL-mediated transcriptional repression of HIF-1alpha. Our findings provide a novel mechanism for the modulation of HIF-1alpha transactivation by pVHL.

Citation

Zaibo Li, Dakun Wang, Xi Na, Susan R Schoen, Edward M Messing, Guan Wu. The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity. The EMBO journal. 2003 Apr 15;22(8):1857-67