Deregulated activation of oncoprotein kinase Tpl2/Cot in HTLV-I-transformed T cells.
Protein kinase Tpl2/Cot is encoded by a protooncogene that is cis-activated by retroviral insertion in murine T cell lymphomas. It has remained unclear whether this oncoprotein kinase is mutated or post-translationally activated in human cancer cells. We have shown here that Tpl2/Cot is constitutively activated in human leukemia cell lines transformed by the human T cell leukemia virus type I (HTLV-I). The kinase activity of Tpl2/Cot is normally suppressed through its physical interaction with an inhibitor, the NF-kappaB1 precursor protein p105. Interestingly, a large pool of Tpl2/Cot is liberated from p105 and exhibits constitutive kinase activity in HTLV-I-transformed T cells. In contrast to its labile property in normal cells, the pathologically activated Tpl2/Cot is remarkably stable. Further, whereas the physiological activation of Tpl2/Cot involves its long isoform, the HTLV-activated Tpl2/Cot is predominantly the short isoform. We have also shown that the HTLV-I-encoded Tax protein is able to activate Tpl2/Cot in transfected cells. Finally, Tpl2/Cot participates in the activation of NF-kappaB by Tax. These findings indicate that deregulated activation of Tpl2/Cot may occur in human cancer cells.
Babu
Geetha
G
Department of Microbiology and Immunology, Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Waterfield
Michael
M
Chang
Mikyoung
M
Wu
Xuefeng
X
Sun
Shao-Cong
SC
D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D016356:Gene Products, tax / Q000378:metabolism; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology*
D016356:Gene Products, tax; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D046988:Proteasome Endopeptidase Complex