Control of the higher eukaryote cell cycle by p34 cdc2 homologues

Abstract

The control of eukaryotic cell proliferation can be conceptually divided into two areas; firstly, those processes, normally involving growth factors in higher eukaryotes, which govern the transition from a resting (G0) state to an actively dividing state, and, secondly, those controls which operate within the cell cycle of the actively dividing cell. While it is the second of these areas which is the major focus for this review, it seems likely that links between elements involved in cell-cycle control and growth factor signal transduction will be elucidated in the near future. Genetic analysis of fission yeast has identified a gene, cdc2, whose product (p34 cdc2 ) is required for traversal of both the G1 and G2 cell-cycle control points and appears to control the timing of mitosis in this organism. p34 cdc2 is a protein kinase whose activity may be regulated by phosphorylation during the cell cycle; genetic evidence suggests that p34 cdc2 may interact directly with the products of two further genes, cdc13 and suc1. Genetic complementation has been used to demonstrate that p34 cdc2 homologues are functionally and structurally conserved in distantly related eukaryotes, and multicellular eukaryotes also contain genes structurally similar to cdc13 and suc1. The p34 cdc2 homologues of multicellular eukaryotes demonstrate potentially regulatory phosphorylation changes through the cell cycle, specifically activatory dephosphorylation on entry into mitosis. They also participate in multiprotein complex formation, as does the p34 cdc2 homologue of budding yeast. Additional long-term control of expression of mammalian p34 cdc2 homologues is likely to be exerted at the transcriptional level. Immunological and biochemical data have demonstrated that p34 cdc2 homologues are the active constituents of both maturation-promoting factor (MPF) and the M-phase (growth-associated) kinase. These data provide the basis of a universal model for the control of the initiation of mitosis in eukaryotic cells; activation of the p34 kinase is proposed to trigger multiple parallel phosphorylation pathways leading to, for example, chromosome condensation, spindle formation and nuclear membrane breakdown. The potential interactions between growth-factor signalling pathways of vertebrates and cell-cycle control through p34 are also discussed.