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

Abstract

IntroductionThe nuclear factor B (NF-B) family of transcription factors plays a central role in regulation of diverse biologic processes, including immune responses, cell growth, and, cell survival. 1 The NF-B factors are usually sequestered in the cytoplasm as latent complexes through physical interaction with the inhibitors of B (IB), mainly IB␣ and the IB-like protein p100 (the precursor of the mature form of NF-B2, p52). Accordingly, inducible degradation of IB␣ and selective degradation of the C-terminal IB-like sequences of p100 (processing) to generate p52 represent 2 major mechanisms leading to NF-B activation: the canonical and noncanonical NF-B pathways, respectively.In the canonical NF-B pathway, IB␣ degradation requires inducible phosphorylation at serines S32 and S36 by a specific IB kinase (IKK) complex that consists of 2 catalytic components, IKK␣ (also known as IKK1) and IKK␤ (or IKK2), and a regulatory subunit, IKK␥ (NEMO). IKK-mediated phosphorylation results in rapid ubiquitination and proteasomal degradation of IB␣, allowing RelA (the prototypic member of NF-B, also known as p65) and other NF-B members to localize to the nucleus to induce gene expression. 1 In the noncanonical NF-B pathway, IKK␣ is specifically recruited into the p100 complex to phosphorylate p100, leading to p100 ubiquitination and processing to p52. The newly generated p52 together with NF-B binding partners then translocates into the nucleus, where they induce or repress gene expression. [2][3][4] Through deregulation of its target genes, NF-B has been linked to various malignancies, such as adult T-cell leukemia (ATL) caused by the human T-cell leukemia virus type I (HTLV-I). 1 This retrovirus encodes a viral oncoprotein Tax, known to persistently activate both the canonical and noncanonical NF-B pathways. Tax binds to and activates IKK via IKK␥ to phosphorylate IB␣, resulting in IB␣ degradation and RelA nuclear translocation. [5][6][7][8][9] Recent studies suggested that posttranslational modifications of Tax, such as ubiquitination, are required for Tax binding to IKK␥ and subsequent IKK activation. [10][11][12] Another important function of Tax in the activation of the canonical NF-B pathway is to promote IKK␣ to phosphorylate S536 of RelA, which is required for RelA transcriptional activity. 13,14 In parallel, Tax specifically recruits IKK␣ into the p100 complex to activate the noncanonical NF-B pathway. 15,16 Although the mechanisms of how the canonical and noncanonical NF-B pathways are regulated and activated under both physiologic and pathogenic conditions have been extensively studied, it remains largely unknown whether and how the 2 NF-B signaling pathways cooperate, particularly during tumorigenesis.The WW domain-containing oxidoreductase (WWOX) gene, also known as WOX1 or FOR, which is located at the second most common human fragile site, FRA16D, has been linked to many different cancer conditions, including leukemia and lymphomas. 17,18 Recent evidence from both biochemical and genetic studies has clearly ...

Introduction to a Thematic Issue for WWOX

“…NF-kB suppresses the expression of WWOX. 27,28 However, transiently overexpressed WW domain induces activation of NF-kB. 15 WWOX modulates the function of transcription factors such as CREB, CRE, cJun, Elk-1 and AP-1.…”

Recurrent alterations of the WW domain containing oxidoreductase gene spanning the common fragile site FRA16D in multiple myeloma and monoclonal gammopathy of undetermined significance

“…In vitro, WWOX inhibits β-catenin (56) and suppresses the transcriptional activity of the nuclear factor-κB (NF-κB)-RELA proto-oncogene, NF-κB subunit complex (57), which are involved in the pathogenesis of MM. Variant WWOX serves as a dominant-negative factor in vitro to inhibit the tumor suppressor function of wild-type WWOX (26).…”

Molecular biology of oncogenic inflammatory processes. I. Non-oncogenic and oncogenic pathogens, intrinsic inflammatory reactions without pathogens, and microRNA/DNA interactions (Review)

“…The WWOX tumor suppressor gene is best understood in its relation to Tax oncoprotein of the human T cell leukemia virus, HTLVI, and osteosarcomagenesis. While the HTLVI Tax oncoprotein activates the NFκB pathways, WWOX inhibits the HTLVI/Tax/NFκB pathway (336). In osteosarcomagenesis, WWOX is frequently absent (silenced; mutated).…”

“…Naturaly, WWOX is activated by its ligand PPXY (P = proline, Y = tyrosine, X = any amino acid, W = tryptophane) (340). WWOX is suppressed in adenocarcinomas other than that of the breast (osteosarcoma, colon cancer, small cell carcinoma of the lung, prostate cancer) (336,337,341343). In small cell carcinoma, it is the BmI1 protein (vide supra) that suppresses WWOX (342).…”