SnapShot: Cell-Cycle Regulators II

Abstract

The core components of the cell-cycle control system are governed by numerous additional regulators, which ensure that cyclin-dependent kinase (Cdk) and anaphase-promoting complex (APC) activities are robustly and rapidly activated in the correct order and at the appropriate cell-cycle stage. Cyclin-Cdk activities are controlled by phosphorylation at inhibitory sites on the Cdk subunit, association with Cdk-inhibitory proteins (CKIs), transcriptional control of cyclins and other regulators, and the ubiquit-in-dependent proteolysis of cyclins and CKIs. APC activity is fine-tuned by inhibitory proteins that restrain its function outside mitosis.A multisubunit ubiquitin ligase called SCF contributes to early cell-cycle control by triggering the ubiquitination and destruction of some CKIs and G1/S cyclins. The SCF core (containing three subunits, not listed here) interacts with numerous F-box proteins that recruit specific substrates for ubiquitination. Typically, SCF targets must be phosphorylated by Cdks or other kinases to allow their recognition by F-box subunits of SCF.Progression through the cell cycle depends in part on transcriptional regulators, including the particularly well-understood regulators of G1/S gene expression at the begin-ning of the cycle. Prior to cell-cycle entry, these regulators interact with inhibitor proteins, blocking the activation of G1/S gene expression and, in some cases, actively repressing it. G1-Cdks phosphorylate and thereby inactivate these inhibitors, unleashing G1/S gene expression.Although the details vary among different species, the general scheme of eukaryotic cell-cycle control can be summarized as follows. In response to the appropriate extracel-lular signals or cell size, G1-Cdks trigger G1/S gene expression, leading to expression of G1/S and S cyclins and other components required for S phase events. G1/S-Cdk activation helps promote S-Cdk activation, at least in some cases, by phosphorylating CKIs and thereby targeting them to SCF for ubiquitination. G1/S- and S-Cdks then collaborate to initiate chromosome duplication and duplication of the spindle poles. M cyclins rise during S phase or thereafter, but M-Cdk complexes are initially restrained in many species by inhibitory phosphorylation by Wee1-related inhibitory kinases. Dephosphorylation by Cdc25-related phosphatases then triggers M-Cdk activation, resulting in mitotic spindle assembly and other preparations for chromosome segregation. When the chromosomes are aligned on the spindle, activation of APC