The tumor suppressor gene WWOX links the canonical and noncanonical NF-?B pathways in HTLV-I Tax-mediated tumorigenesis.

ABSTRACT: Both the canonical and noncanonical nuclear factor ?B (NF-?B) pathways have been linked to tumorigenesis. However, it remains unknown whether and how the 2 signaling pathways cooperate during tumorigenesis. We report that inhibition of the noncanonical NF-?B pathway significantly delays tumorigenesis mediated by the viral oncoprotein Tax. One function of noncanonical NF-?B activation was to repress expression of the WWOX tumor suppressor gene. Notably, WWOX specifically inhibited Tax-induced activation of the canonical, but not the noncanonical NF-?B pathway. Mechanistic studies indicated that WWOX blocked Tax-induced inhibitors of ?B kinase? (IKK?) recruitment to RelA and subsequent RelA phosphorylation at S536. In contrast, WWOX Y33R, a mutant unable to block the IKK? recruitment and RelA phosphorylation, lost the ability to inhibit Tax-mediated tumorigenesis. These data provide one important mechanism by which Tax coordinates the 2 NF-?B pathways for tumorigenesis. These data also suggest a novel role of WWOX in NF-?B regulation and viral tumorigenesis.

SUBMITTER: Fu J 

PROVIDER: S-EPMC3318777 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature