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Modern Genetic Analysis Chapter 15. Regulation of Cell Number: Normal and Cancer Cells
The Cell Proliferation Machinery
The Cell Cycle

There are four main parts to the cell cycle: M phasemitosis, the cell division process described in detail in Chapter 4and three parts that are components of interphaseG1, the gap period between the end of mitosis and the start of DNA replication; S, the period during which DNA synthesis occurs; and G2, the gap period following DNA replication and preceding the initiation of the mitotic prophase. In mammals, where the cell cycle is particularly well studied, differences in the rate of cell division are largely due to differences in the length of time between entering and exiting G1. This variation is due to an optional G0 resting phase into which G1-phase cells can shunt and remain for variable lengths of time, depending on the cell type and on environmental conditions. Conversely, S, G2, and M phases are normally quite fixed in duration. In this section, we consider the molecules that drive the cell cycle. In a later section, we shall consider how these molecules are integrated into the overall biology of the cell.

Cyclins and Cyclin-Dependent Protein Kinases

The engines that drive progression from one step of the cell cycle to the next are a series of protein complexes composed of two subunits: a cyclin and a cyclin dependent protein kinase (abbreviated CDK). In every eukaryote, there is a family of structurally and functionally related cyclin proteins. Cyclins are so named because each is found only during one or another segment of the cell cycle. The onset of the appearance of a specific cyclin is due to cell cycle controlled transcription, in which the previously active cyclinCDK complex leads to the activation of a transcription factor that activates the transcription of this new cyclin. The disappearance of a cyclin depends on three events: rapid inactivation of the activator of transcription of this cyclin's gene (so that no new mRNA is produced), a high degree of instability of the cyclin mRNA (so that the existing pool of mRNA is eliminated), and a high level of instability of the cyclin itself (so that the pool of cyclin protein is destroyed).

Cyclin-dependent protein kinases also constitute a family of structurally and functionally related proteins. Kinases are enzymes that add phosphate groups to target substrates; for protein kinases such as CDKs, the substrates are proteins. CDKs are so named because their activities are regulated by cyclins and because they catalyze the phosphorylation of specific serine and threonine residues of specific target proteins.

The target proteins for CDK phosphorylation are determined by the associated cyclin. In other words, the cyclin tethers the target protein so that the CDK can phosphorylate it (Figure 15-1), thereby changing the activity of each target protein. Because different cyclins are present at different phases of the cell cycle (Figure 15-2 on the next page), different phases of the cell cycle are characterized by the phosphorylation of different target proteins. The phosphorylation events are transient and reversible. When the cyclinCDK complex disappears, the phosphorylated substrate proteins are rapidly dephosphorylated by protein phosphatases.

CDK Targets

How does the phosphorylation of some target proteins control the cell cycle? Phosphorylation initiates a chain of events that culminates in the activation of certain transcription factors. These transcription factors promote the transcription of certain genes whose products are required for the next stage of the cell cycle. Much of our knowledge of the cell cycle comes from both genetic studies in yeast (see Genetics in Process 15-1) and from biochemical studies of cultured mammalian cells. A well-understood example is the RbE2F pathway in mammalian cells. Rb is the target protein of a CDKcyclin complex called Cdk2cyclin A, and E2F is the transcription factor that Rb regulates (Figure 15-3). From late M phase through the middle of G1, the Rb and E2F proteins are combined in a protein complex that is inactive in promoting transcription. In late G1, the Cdk2cyclin A complex is produced and phosphorylates the Rb protein. This phosphorylation produces a change in the shape of Rb such that it can no longer bind to the E2F protein. The free E2F protein is then able to promote transcription of certain genes that encode enzymes vital for DNA synthesis. This allows the next phase of the cell cycleS phaseto proceed.

Rb and E2F are in fact representatives of two families of related proteins. In mammals, different cyclin CDK complexes (Figure 15-2) are thought to selectively phosphorylate different proteins of the Rb family, each of which in turn releases the specific E2F family member to which it is bound. The different E2F transcription factors then promote the transcription of different genes that execute different aspects of the cell cycle.

MESSAGE
Sequential activation of different CDKcyclin complexes ultimately controls progression of the cell cycle.

© 1999 by W. H. Freeman and Company. All rights reserved.