Activation of NF-kappaB by HTLV-I and implications for cell transformation.
T-cell transformation by the human T-cell leukemia virus type I (HTLV-I) involves deregulation of cellular transcription factors, including members of the NF-kappaB family. In normal T cells, NF-kappaB activation occurs transiently in response to immune stimuli, which is required for antigen-stimulated T-cell proliferation and survival. However, HTLV-I induces persistent activation of NF-kappaB, causing deregulated expression of a large array of cellular genes, which in turn contributes to the induction of T-cell transformation. The HTLV-I transforming protein Tax functions as an intracellular stimulator of IkappaB kinase (IKK), a cellular kinase mediating NF-kappaB activation by diverse stimuli. Tax physically interacts with IKK and renders this inducible kinase constitutively active. By assembling different Tax/IKK complexes, Tax targets the persistent activation of both canonical and noncanonical NF-kappaB signaling pathways. Whereas Tax plays a primary role in HTLV-I-mediated NF-kappaB activation, recent studies reveal that the IKK/NF-kappaB signaling pathway is also activated in freshly isolated adult T-cell leukemia (ATL) cells that often lack detectable Tax expression. The mechanism underlying this Tax-independent pathway of NF-kappaB activation remains poorly understood. Clarifying the precise nature and consequences of the constitutive NF-kappaB activation in ATL cells is important for developing rational therapeutic strategies for this T-cell malignancy.
Sun
Shao-Cong
SC
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, PA 17033, USA. sxs70@psu.edu
Yamaoka
Shoji
S
D000818:Animals; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000628:therapy / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology
D016328:NF-kappa B