Molecular Mechanisms of Cell Cycle Control

Cell cycle events are controlled by a network of molecular signals, whose central components are cyclin-dependent protein kinases (Cdks). Cdks, when paired with suitable cyclin partners, phosphorylate many target proteins involved in cell cycle events (Figure 10.2A). For instance, by phosphorylating proteins bound to chromosomes at "origins of replication" (specific nucleotide sequences, where DNA replication can start), Cdks

Figure 10.2 Cyclin-dependent kinase. (A) The role of a cyclin-dependent kinase (Cdk) is to phospho-rylate certain target proteins using ATP as the phosphate donor. Cdk requires a cyclin partner in order to be active and to recognize proper targets. Cdk targets include proteins involved in DNA replication, chromosome condensation, spindle formation, and other crucial events of the cell cycle. (B) Cdk activity can be regulated in three ways: By availability of cyclin subunits, by phosphorylation of the Cdk subunit, and by stoichiometric binding to inhibitors (CKI = cyclin-dependent kinase inhibitor).

Figure 10.2 Cyclin-dependent kinase. (A) The role of a cyclin-dependent kinase (Cdk) is to phospho-rylate certain target proteins using ATP as the phosphate donor. Cdk requires a cyclin partner in order to be active and to recognize proper targets. Cdk targets include proteins involved in DNA replication, chromosome condensation, spindle formation, and other crucial events of the cell cycle. (B) Cdk activity can be regulated in three ways: By availability of cyclin subunits, by phosphorylation of the Cdk subunit, and by stoichiometric binding to inhibitors (CKI = cyclin-dependent kinase inhibitor).

trigger the onset of DNA synthesis. By phosphorylating histones (proteins involved in DNA packaging), Cdks initiate chromosome condensation at the G2-M transition. Clearly, to understand the timing of these basic cell cycle events, one must understand the patterns of activation and inactivation of Cdks.

Cdk activities can be regulated throughout the cell cycle in many ways (Figure 10.2B). In principle, cells could regulate the availability of Cdk subunits, but this is uncommon; most Cdks are present in constant abundance throughout the cell cycle. Their activity is regulated, instead, by the availability of cyclin partners. Cyclin abundance is determined by the rates of cyclin synthesis and degradation, both of which can be regulated during the cell cycle, as we shall see. Secondly, Cdk/cyclin dimers can be put out of commission by binding a third partner, a stoichiometric inhibitor, generally referred to as a CKI (cyclin-dependent kinase inhibitor). CKIs come and go, because their synthesis and degradation rates are also cell-cycle regulated. Finally, Cdk activity can be inhibited by phosphorylation of a specific tyrosine residue, and the phosphory-lation state of Cdk varies during the cell cycle as the activities of the tyrosine kinase (Weel) and tyrosine phosphatase (Cdc25) fluctuate.

Because cells of higher eukaryotes contain many different Cdks and cyclins, "combinatorics" might play a major role in cell cycle progression, as the Cdk and cyclin subunits change partners. However, lower eukaryotes accomplish all the same basic tasks with many fewer components (one Cdk and 2-4 crucial cyclins), indicating that one Cdk is sufficient and that Cdk/cyclin holoenzymes can substitute for one another, to a large extent. Thus, progress through the cell cycle is not just a "square dance," with Cdks and cyclins swapping partners to a steady rhythm, as some textbook dia grams might suggest, but rather a complex, nonlinear, dynamical system of interactions between Cdk/cyclin dimers and their regulatory agents: transcription factors, degradation machinery, CKIs, and tyrosine-modifying enzymes. Our task will be to understand the basic principles of this dynamical system, but first we need some more mechanistic details.

Nasmyth's two cell-cycle states shown in Figure 10.1, G1 and S-G2-M, are correlated with low and high Cdk activity, respectively. Cdk activity is low in G1 because its obligate cyclin partners are missing. Cyclin levels are low in G1 because cyclin mRNA synthesis is inhibited and cyclin protein is rapidly degraded. At Start, cyclin synthesis is induced and cyclin degradation inhibited, causing a dramatic rise in Cdk activity, which persists throughout S, G2, and M. The initial rise in Cdk activity is sufficient to initiate DNA replication, but further increase is required to drive cells into mitosis [Stern and Nurse, 1996].

At Finish, a group of proteins, making up the anaphase-promoting complex (APC), is activated. The APC attaches a "destruction label" to specific target proteins, which are subsequently degraded by the cell's proteolytic machinery. The APC consists of a core complex of about a dozen polypeptides plus two auxiliary proteins, Cdc20 and Cdh1, whose apparent roles (when active) are to recognize specific target proteins and present them to the core complex for labeling. Activation of Cdc20 at Finish is necessary for degradation of cohesins at anaphase, and for activation of Cdh1. Together, Cdc20 and Cdh1 label cyclins for degradation at telophase, allowing the control system to return to G1. We must distinguish between these two different auxiliary proteins, because Cdc20 and Cdh1 are controlled differently by cyclin/Cdk, which activates Cdc20 and inhibits Cdh1.

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