The eukaryotic cell cycle has been divided into two "active" phases, DNA replication (S phase) and mitosis (M phase), and two gap phases, G1 and G2 (Howard and Pelc 1953). The G1 phase delimits the previous mitosis from entry into the next S phase, whereas the G2 phase separates the S phase from the subsequent M phase. The progression into each of the active phases is permitted only upon completion of the previous active phase; the major regulatory points in the cell cycle operate at the G1/S and G2/M boundaries. These regulatory points are governed by a class of serine-threonine protein kinases, which require binding of regulatory protein, cyclin, and are therefore designated cyclin-dependent kinases (CDKs).
CDKs are homologs of proteins encoded in fission yeast by the cdc2 locus and in budding yeast by CDC28. In both yeasts only one CDK, possessing a canonical PSTAIRE motif in its cyclin-binding domain, is sufficient to drive the cell cycle (Mendenhall and Hodge 1998; Moser and Russell 2000). However, cell cycle regulation in more complex models requires activity of several CDKs. In humans, there are three PSTAIRE CDKs (CDK1/cdc2, CDK2, and CDK3) and a variant CDK4/6 subfamily with a P(I/L)ST(V/I)RE motif, all of which function in cell cycle regulation (Meyerson et al. 1992; Pines 1995; Reed 1997; Lee and Yang 2003). Higher plants encode two subclasses of CDK involved in the cell cycle regulation, CDKA and CDKB. CDKA, the better characterized of the two, possesses a PSTAIRE motif. CDKA is ubiquitously expressed in dividing tissues (Fobert et al. 1996; Segers et al. 1996) and in suspension cells (Martinez et al. 1992; Hemerly et al. 1993; Magyar et al. 1997; Richard et al. 2001; Sorrell et al. 2001; Menges et al. 2002, 2003; Menges and Murray 2002) and can functionally substitute for its ortholog cdc2/CDC28 in both budding and fission yeast (Ferreira et al. 1991; Hirt et al. 1991). B-type CDKs are unique to plants and algae (Mironov et al. 1999); they are expressed exclusively during G2 and M phase (Fobert et al. 1996; Segers et al. 1996; Magyar et al. 1997; Porceddu et al. 2001; Sorrell et al. 2001; Menges and Murray 2002; Lee et al. 2003; Boudolf et al. 2004). This expression pattern is unique to plant CDKBs and has not been observed for any type of CDKs in other eukaryotes (Dewitte and Murray 2003).
CDKs are activated by binding to the cyclins (Sherr 1994). As the name implies, the cyclins' accumulation levels oscillate during the cell cycle; cyclin accumulation levels are regulated both transcriptionally and posttranslation-ally. There are three main classes of cyclins: G1, S, and M phase-specific cyclins. G1-specific D-type cyclins are not conserved between animals and plants while S-phase-specific A-type and M-phase-specific B-type cyclins are orthologous in animals and plants (for review see Renaudin et al. 1996; Mironov et al. 1999; Murray 2004).
The activity of the CDK-cyclin complexes is further regulated by binding of the complex by inhibitor proteins and phosphorylation of CDKs themselves (Morgan 1995). The phosphorylation of CDK is mediated by two groups of proteins: cyclin-dependent activating kinases (CAKs) and Wee1 kinases. CAKs are responsible for the activating phosphorylation within the T-loop of the CDKs (Ducommun et al. 1991; Gould et al. 1991). On the contrary, Wee1 kinase executes the inhibitory phosphorylation within the ATP-binding site of CDK (Gould and Nurse 1989; Jin et al. 1996). Phosphorylation by Wee1 enables the inactivation of CDKs until the G2/M transition, when they are abruptly dephosphorylated by Cdc25 phosphatase leading to the activation of CDK-cyclin complexes and triggering of mitosis (Russell and Nurse 1986, 1987; Kumagai and Dunphy 1991).
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