Journal
BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE
Volume 86, Issue 3, Pages 227-234Publisher
CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS
DOI: 10.1139/O08-035
Keywords
VHL; integrin; adherens junctions; tight junctions; HIF
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Funding
- NCI NIH HHS [R01 CA085412, CA85412] Funding Source: Medline
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Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene occurs in the majority of clear-cell renal cell carcinomas (RCCs). It was previously shown that VHL decreased the abundance of integrins alpha 2, alpha 5, and beta 1, which is consistent with VHL-associated changes in cell-cell and cell - extracellular matrix adhesions. We investigated the mechanism by which VHL downregulates integrins. Although VHL can target hypoxia-inducible factor alpha (HIF alpha) subunits for degradation, VHL-dependent reduction of integrins was independent of O(2) concentration and HIF alpha levels. VHL reduced the half-lives of integrins, and this activity was blocked by proteasomal inhibition. Although ectopically expressed FLAG-VHL retained HIF alpha degradation activity, it neither downregulated integrins nor promoted adherens and tight intercellular junctions, in contrast to expressed wild-type VHL. Moreover, integrins co-immunoprecipitated with wild-type VHL, but not FLAG-VHL. These data indicate that the downregulation of integrins by VHL is distinct from the regulation of HIF alpha subunits by VHL, and suggests that the loss of this activity contributes to VHL-associated RCC development through disruption of adherens and tight junctions.
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