Cyclins are so named because their concentrations change during the cell cycle. They form a family of proteins that is defined by three key features:

Cyclins are divided into four classes defined by their presence and activity during specific phases of the cell cycle: G₁ cyclins, G₁/S phase cyclins, S phase cyclins, and mitotic cyclins (see Table 19-1). The different types of cyclins are quite distinct from one another in protein sequence, but all of them contain a conserved 100-amino-acid region known as the cyclin box and possess similar three-dimensional structures.

The G₁ cyclins are the linchpin in coordinating the cell cycle with extracellular events. Their activity is subject to regulation by signal transduction pathways that sense the presence of growth factors or cell proliferation inhibitory signals. In metazoans, G₁ cyclins are known as cyclin Ds, and they bind to CDK4 and CDK6. G₁ cyclins are unusual in that their levels do not show strong fluctuation, as levels of other cyclins do. Instead, in response to macromolecule biosynthesis and extracellular signals, their levels gradually increase throughout the cell cycle.

The G₁/S cyclins accumulate during late G₁, reach peak levels when cells enter S phase, and decline during S phase (see Figure 19-10). They are known as cyclin E in metazoans and bind to CDK2. The main function of cyclin E–CDK2 complexes, together with cyclin D–CDK4/6, is to trigger the G₁–S phase transition. This transition, known as START in yeast and the restriction point in mammalian cells, is defined as the point at which cells are irreversibly committed to cell division and can no longer return to the G₁ state. In molecular terms, this means that cells initiate DNA replication as well as duplicating their centrosomes, which is the first step in the formation of the mitotic spindle that will be used during mitosis.

S phase cyclins are synthesized concomitantly with G₁ cyclins, but their levels remain high throughout S phase and do not decline until early mitosis. Two types of S phase cyclins trigger S phase in metazoans: cyclin E, which can also promote entry into the cell cycle and is therefore also a G₁/S cyclin, and cyclin A. Both cyclins bind CDK2 (see Table 19-1) and are directly responsible for DNA synthesis. As we will see in Section 19.4, these protein kinases phosphorylate proteins that activate DNA helicases and load polymerases onto DNA.

Mitotic cyclins bind CDK1 to promote entry into and progression through mitosis. The metazoan mitotic cyclins are cyclins A and cyclins B (note that cyclin A can also trigger S phase when bound to CDK2). Mitotic cyclin-CDK complexes are synthesized during S phase and G₂, but as we will see shortly, their activities are held in check until DNA synthesis is completed. In Section 19.5, we will see that once activated, mitotic CDKs promote entry into mitosis by phosphorylating and activating hundreds of proteins to promote chromosome condensation, nuclear envelope breakdown, mitotic spindle formation, and other aspects of mitosis. Their inactivation during anaphase prompts cells to exit mitosis, which involves the disassembly of the mitotic spindle, chromosome decondensation, the re-formation of the nuclear envelope, and eventually cytokinesis.

885

Mitotic cyclins were the first cyclins to be discovered, and it was their characterization that led to the discovery of the oscillatory nature of the activities that govern cell cycle progression (see Classic Experiments 19-1 and 19-2). Subsequent studies showed that G₁/S phase cyclins had similar properties. Their expression is sufficient to promote entry into the cell cycle, and therefore all the other proteins needed for cell cycle entry are present in unlimited amounts. It is thus clear that the regulation of cyclin levels is an essential aspect of the eukaryotic cell cycle. As we will see in the following section, cells use multiple mechanisms to restrict cyclins to the appropriate cell cycle stage and to keep them at the right concentration.