The tumor suppressor gene WWOX links the canonical and noncanonical NF-κB pathways in HTLV-I Tax-mediated tumorigenesis.
Both the canonical and noncanonical nuclear factor κB (NF-κB) 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-κB pathway significantly delays tumorigenesis mediated by the viral oncoprotein Tax. One function of noncanonical NF-κB 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-κB pathway. Mechanistic studies indicated that WWOX blocked Tax-induced inhibitors of κB kinaseα (IKKα) recruitment to RelA and subsequent RelA phosphorylation at S536. In contrast, WWOX Y33R, a mutant unable to block the IKKα 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-κB pathways for tumorigenesis. These data also suggest a novel role of WWOX in NF-κB regulation and viral tumorigenesis.
University of Pittsburgh Cancer Institute, Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, PA 15213, USA.
Jing
J
Fu
Zhaoxia
Z
Qu
Pengrong
P
Yan
Chie
C
Ishikawa
Rami I
RI
Aqeilan
Arnold B
AB
Rabson
Gutian
G
Xiao
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D016356:Gene Products, tax / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D015490:HTLV-I Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000235:genetics; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D019169:Jurkat Cells; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074584:WW Domain-Containing Oxidoreductase
D016356:Gene Products, tax; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C428130:Wwox protein, mouse; D051550:I-kappa B Kinase