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Identification of the RNA polymerase II subunit hsRPB7 as a novel target of the von Hippel—Lindau protein

Xi Na, Hai Ou Duan, Edward M. Messing, Susan R. Schoen, Charlotte K. Ryan, P.Anthony di Sant'Agnese, Erica A. Golemis, Guan Wu

Author Affiliations

  1. Xi Na1,2,
  2. Hai Ou Duan2,
  3. Edward M. Messing1,2,3,
  4. Susan R. Schoen1,
  5. Charlotte K. Ryan2,
  6. P.Anthony di Sant'Agnese2,
  7. Erica A. Golemis4 and
  8. Guan Wu*,1,2,3
  1. 1 Department of Urology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 656, Rochester, NY, 14642, USA
  2. 2 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, NY, 14642, USA
  3. 3 The James P. Wilmot Cancer Center, University of Rochester Medical Center, 601 Elmwood Avenue, Box 656, Rochester, NY, 14642, USA
  4. 4 Division of Basic Sciences, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
  1. *Corresponding author. E-mail: Guan_Wu{at}urmc.rochester.edu
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Abstract

Inactivation of the von Hippel—Lindau (VHL) tumor suppressor gene is linked to the hereditary VHL disease and sporadic clear cell renal cell carcinomas (CCRCC). VHL‐associated tumors are highly vascularized, a characteristic associated with overproduction of vascular endothelial growth factor (VEGF). The VHL protein (pVHL) is a component of the ubiquitin ligase E3 complex, targeting substrate proteins for ubiquitylation and subsequent proteasomic degradation. Here, we report that the pVHL can directly bind to the human RNA polymerase II seventh subunit (hsRPB7) through its β‐domain, and naturally occurring β‐domain mutations can decrease the binding of pVHL to hsRPB7. Introducing wild‐type pVHL into human kidney tumor cell lines carrying endogenous mutant non‐functional pVHL facilitates ubiquityl ation and proteasomal degradation of hsRPB7, and decreases its nuclear accumulation. pVHL can also suppress hsRPB7‐induced VEGF promoter transactivation, mRNA expression and VEGF protein secretion. Together, our results suggest that hsRPB7 is a downstream target of the VHL ubiquitylating complex and pVHL may regulate angiogenesis by targeting hsRPB7 for degradation via the ubiquitylation pathway and preventing VEGF expression.

  • Received July 16, 2002.
  • Revision received June 25, 2003.
  • Accepted June 30, 2003.
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