Regulation of cyclin-dependent kinases

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We have investigated in vivo regulation and function of Cdk-cyclin complexes and their regulators.1. Signalling pathways that lead to activation of cyclin B-Cdc2 have been studied at entry into various M- phases during meiotic and early embryonic cell cycles in starfish oocytes and eggs. Each signalling pathway is found to be composed of Akt/PKB-cyclin B-Cdc2 Plkl at the first meiosis, MAPK--Plkl-- cyclin B-Cdc2 at the second meiosis, and cyclin A-Cdc2-Plkl-cyclin B-Cdc2 at embryonic mitosis. In all of these pathways, a major target of Plkl is not Cdc25 but Mytl. These findings identify Akt/PKB with a novel role for a trigger kinase of M-phase, and also Plkl with novel upstream and downstream pathways.2. Regulatory mechanisms have been studied how the activity of cyclin B-Cdc2 is maintained at elevated levels in metaphase-II arrest (CSF, cytostatic factor, arrest) of Xenopus oocytes. In contrast to the report by P. Jackson's group indicating that Emil is an essential component of CSF, we have demonstrated that in oocytes arresting at metaphase-II, Emil is undetectable and the APC/C is even functional, thus providing the study of CSF arrest with novel viewpoints.3. Roles of Jabl for cell proliferation control have been studied in mammalian somatic cells. We have demonstrated : (1) Jabl promotes nuclear export and the resulting destruction of the Cdk inhibitor, p27, through binding to both CRM1 and p27 ; (2) Jabl is over expressed and activated in myelocytic leukemia, pancreatic cancer and lung cancer, accompanied with unusal destruction of p27 and accerelation of malignancy ; (3) Jabl-knockout mice are embryonic lethal, accompanied with over expression of cyclin E, p53, and p27 which might cause inhibition of cell proliferation and activation of apoptosis ; (4) Jabl transgenic mice suffer leukemia, possibly due to perturbed expression and intracellular localization of p27 andp16.