The paradigm of cell-cycle control

The collective results from studies in various eukaryotes have demonstrated that progression through the cell-division cycle is driven by activation and inactivation of cyclin-dependent kinases (CDKs), which trigger the transition to subsequent phases of the cycle. CDKs are small serine/threonine protein kinases that require association with a cyclin subunit for their activation. In yeast, a single CDK (p34CDC28 in Saccharomyces cerevisiae and p34cdc2 in Schizosaccharomyces pombe) acts with different cyclins to promote progression through G1, S and G2/M. Metazoans, including C. elegans, use not only a variety of cyclins but also multiple catalytic subunits (Figure 1C).
Many levels of regulation impinge upon the CDKs to impose tight control over cell-cycle progression. Such regulation involves controlled expression and destruction of cyclins, activating and inhibitory phosphorylation and dephosphorylation of the CDKs, and expression and destruction of inhibitory proteins that associate with CDKs, or CDK/cyclin complexes (Figure 2).
figure 2
Figure 2. Model illustrating general aspects of CDK regulation. CDK activation requires cyclin (CYC) expression and association. Cyclin/CDK complexes are kept inactive through association with CDK-inhibitory proteins (CKIs) and inhibitory phosphorylation by Wee1/Myt1 kinases (black circles). Activation requires ubiquitin-dependent proteolysis of the CKI, phosphorylation of the CDK by a CDK-activating kinase (CAK; red circle), and removal of the inhibitory phosphates by a Cdc25 phosphatase. Cyclin destruction leads to inactivation. Ubiquitin-dependent proteolysis of cell cycle regulators in late G1 and S involves cullin-based E3 ligases such as SCF, while in M phase and early G1 the anaphase-promoting complex (APC) is active. The exclamation figure denotes the active kinase complex, the large arrow indicates time.
The paradigm for cell-cycle regulation through activation and inactivation of CDKs applies to all eukaryotes. However, differences do exist: certain control elements, such as the CDK inhibitory proteins (CKIs), show little resemblance between yeast and mammals. In addition, some regulators are absent in single cell eukaryotes, including the pRb and E2F families, and nearly all regulatory genes have expanded into subfamilies with multiple members in mammals. Studies over the last decade have shown that cell-cycle control in C. elegans uses well-recognizable homologs of nearly all mammalian regulators, often represented by just a single member (Table 1). As an exception to the rule, the pINK family of Cdk4/6 kinase inhibitors has not as yet been identified in C. elegans. Genetic studies have placed the C. elegans cell-cycle genes into pathways that resemble those in mammals, and novel regulatory elements have been discovered.

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