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  • Meeting abstract
  • Open Access

Coordination of the canonical and noncanonical IKK/NF-κB signaling pathways in HTLV-I Tax-mediated tumorigenesis

  • 1,
  • 1,
  • 1,
  • 1,
  • 1,
  • 2,
  • 3,
  • 2,
  • 4 and
  • 1Email author
Retrovirology20118 (Suppl 1) :A157

https://doi.org/10.1186/1742-4690-8-S1-A157

  • Published:

Keywords

  • Cooperative Role
  • RelA Phosphorylation
  • Subsequent RelA
  • WWOX Tumor Suppressor

Although the mechanisms by which the HTLV-I Tax oncoprotein activates the two NF-κB signaling pathways have been well studied, there is still no convincing evidence demonstrating a functional role for NF-κB in the Tax-mediated tumorigenesis or HTLV-I-mediated adult T-cell leukemia/lymphoma (ATL). Moreover, how Tax is negatively regulated by cellular factors has not yet been explored. Using various transgenic mice and cells deficient in different key IKK/NF-κB signaling components, we have defined the differential but cooperative roles of the canonical and noncanonical NF-κB pathways in Tax-mediated tumorigenesis. One function of non-canonical NF-κB activation is to repress expression of the wwox tumor suppressor gene, which in turn facilitates Tax-induced canonical NF-κB activation. Mechanistic studies indicate that WWOX blocks Tax-induced IKKalpha recruitment and subsequent RelA phosphorylation. Furthermore, we have identified PDLIM2, an essential terminator of canonical NF-κB activation, as a negative regulator of Tax. PDLIM2 directly binds to and shuttles Tax from its activation sites to the nuclear matrix for ubiquitination-mediated degradation, thereby suppressing the tumorigenicities of HTLV-I- or Tax-transduced cells. Interestingly, PDLIM2 expression is epigenetically downregulated in HTLV-I-transformed T cells and primary ATL cells. These studies suggest that the counterbalance between PDLIM2 and HTLV-I may determine the ATL leukemogenesis and provide the first line of genetic evidence demonstrating the functional significance of NF-κB in Tax-mediated tumorigenesis. These studies also define, for the first time, a delicate cooperation of the two pro-oncogenic NF-κB pathways in tumorigenesis and a functional role of the WWOX tumor suppressor in NF-κB regulation and viral tumorigenesis.

Declarations

Acknowledgements

This work was supported in part by NIH/NCI R01 CA116616 and ACS RSG-06-066-01-MGO to GX.

Authors’ Affiliations

(1)
University of Pittsburgh Cancer Institute, Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
(2)
Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, Okinawa, Japan
(3)
The Lautenberg Center for General and Tumor Immunology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
(4)
Child Health Institute of New Jersey, Departments of Pediatrics, Molecular Genetic, Microbiology and Immunology, UNDNJ-RWJMS, New Brunswick, NJ, USA

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