p27kip protein levels and E2F activity are targets of Cot kinase during G1 phase progression in T cells.
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 G(0) to G(1) 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 G(1) 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 G(2)-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 G(1) progression events by Cot kinase.
Velasco-Sampayo
A
A
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Cientificas, Facultad. Medicina Universidad Autónoma de Madrid, Madrid, Spain.
Alemany
S
S
D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004261:DNA Replication / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D050684:E2F Transcription Factors; D016193:G1 Phase / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D005822:Genetic Vectors / Q000138:chemical synthesis / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human