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


ABSTRACT: 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.

SUBMITTER: Li Z 

PROVIDER: S-EPMC154465 | biostudies-literature | 2003 Apr

REPOSITORIES: biostudies-literature

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

Li Zaibo Z   Wang Dakun D   Na Xi X   Schoen Susan R SR   Messing Edward M EM   Wu Guan G  

The EMBO journal 20030401 8


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 Kr  ...[more]

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