DYNAMICS OF THE CELL-CYCLE ENGINE - CDK2-KINASE AND THE TRANSITION INTO MITOSIS

The autonomous cell divisions during the early development of Xenopus laevis is believed to comprise a universal cell cycle engine. Recent e xperimental data indicates that the Cdk2-cyclin E kinase is required f or the rapid divisions during Xenopus embryogenesis and that the compl ex is crucial for the transition into mitosis. In the present paper, t he activity of Cdk2-cyclin E is incorporated into an existing comprehe nsive model of the cell cycle engine as an activity operating in paral lel with the mitosis promotion factor (MPF) on the phosphatase Cdc25. This introduces interesting regulatory and dynamic properties for the transition into mitosis that reveals new insight into the mechanisms o f the cell division process. It is shown that the Cdk2-cyclin E comple x can act as an effective modulator of the threshold MPF activity need ed to initiate mitosis. When the Cdk2-cyclin E activity is below a cri tical value, the cell cycle arrests in a well-defined state of low MPF activity corresponding to G2 arrest. In agreement with experiments a single mitotic event occurs following injection of free cyclin B. Abov e a critical activity, the presence of Cdk2-cyclin E allows for sustai ned oscillations corresponding to repeated cell divisions and the Cdk2 -cyclin E may be the cause for the suppressed G2 checkpoint in the ear ly embryonic cell cycles. A detailed bifurcation analysis reveals that the transition from steady to oscillatory behavior involves a homocli nic orbit of infinite period through an omega explosion. The general p roperties of the omega explosion explain the bifurcation as a dynamic mechanism well-suited for the G2 checkpoint and suggest a plausible ex planation for the elongation of the cell cycle as observed at the mid- blastula transition. The proposed mechanism also suggests a plausible explanation of G2 checkpoint failure following DNA damage in human cel ls overexpressing Cdk2 and we suggest that the onset of mitosis in the mammalian cell occurs as the result of a slow passage through a criti cal point. (C) 1998 Academic Press.