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p27^kif Protein Levels and E2F Activity Are Targets of Cot Kinase During G₁ Phase Progression in T Cells¹

Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Cientificas, Facultad. Medicina Universidad Autónoma de Madrid, Madrid, Spain

Cot/Tpl-2 kinase, homologous to members of mitogen-activated protein kinase kinase kinase, was initially discovered by its capacity to promote cell transformation. Cot/Tpl-2 mRNA levels are increased during G₀ to G₁ phase progression in T lymphocytes, suggesting a role for this kinase later on in the cell cycle. The IL-2-dependent CTLL-2 cells were used to investigate the role of Cot kinase in G₁ to S phase transition. Transient expression of Cot kinase in CTLL-2 cells increases DNA synthesis triggered by IL-2 and the transient expression of a dominant negative form of Cot kinase in CTLL-2 markedly reduces the DNA synthesis triggered by this cytokine. Cell cycle analysis of synchronized CTLL-2 stabling overexpressing Cot kinase indicates that this kinase contributes to the passage to S and G₂-M phases of the cell cycle. Cot kinase reduces the levels of the cyclin kinase inhibitor p27^kip, whereas bcl-x_L expression is unaffected. Cot kinase also increases E2F transcriptional activity in a phosphatidylinositol 3 kinase-independent way and acts in synergy with this kinase. These data give evidence, for the first time, of the regulation of different G₁ progression events by Cot kinase.

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