Tax-independent constitutive IkappaB kinase activation in adult T-cell leukemia cells.
Adult T-cell leukemia (ATL) is a fatal T-cell malignancy that arises long after infection with human T-cell leukemia virus type I (HTLV-I). We reported previously that nuclear factor-kappaB (NF-kappaB) was constitutively activated in ATL cells, although expression of the viral proteins was barely detectable, including Tax, which was known to persistently activate NF-kappaB. Here we demonstrate that ATL cells that do not express detectable Tax protein exhibit constitutive IkappaB kinase (IKK) activity. Transfection studies revealed that a dominant-negative form of IKK1, and not of IKK2 or NF-kappaB essential modulator (NEMO), suppressed constitutive NF-kappaB activity in ATL cells. This IKK activity was accompanied by elevated expression of p52, suggesting that the recently described noncanonical pathway of NF-kappaB activation operates in ATL cells. We finally show that specific inhibition of NF-kappaB by a super-repressor form of IkappaBalpha (SR-IkappaBalpha) in HTLV-I-infected T cells results in cell death regardless of Tax expression, providing definitive evidence of an essential role for NF-kappaB in the survival of ATL cells. In conclusion, the IKK complex is constitutively activated in ATL cells through a cellular mechanism distinct from that of Tax-mediated IKK activation. Further elucidation of this cellular mechanism should contribute to establishing a rationale for treatment of ATL.
Hironaka
Noriko
N
Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Mochida
Kanako
K
Mori
Naoki
N
Maeda
Michiyuki
M
Yamamoto
Naoki
N
Yamaoka
Shoji
S
D016923:Cell Death; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D016356:Gene Products, tax / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
D016356:Gene Products, tax; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human