Regulation of the Cell Cycle

Eucaryotic cells execute their reproduction in a cyclic process, in which at least two phases, a S phase and a M phase, can be differentiated on the basis of biochemical and morphological features. The biochemical characteristic of the S (synthesis) phase is the replication of nuclear DNA and thus doubling of the genetic information. In M (mitosis) phase, division of the chromosomes between the daughter cells is prepared and carried out. 

In most cell types, two further phases can be distinguished, Gi and G2 phase. Gi phase includes the period between M phase and S phase G2 phase covers the period between S phase and M phase. From Gi phase, the cell may transfer into a quiescent state known as Go phase. Appropriate signals (e.g., addition of growth factors) can induce the cell to return from Go into Gi phase and proceed with the cell cycle. 

The cyclical sequence of Gi, S, G2 and M phases describes a standard cell cycle (Fig. 13.1). Rapidly dividing cells in mammals require 12-24 h for completion of a cell cycle. 

In some cell types, such as early embryonal cells, the period between the S and M phases is reduced to the extent that discrete Gi and G2 phases cannot be identified. The duration of the cell cycle is then only 8-60 min. 

Morphologically, cell division is only visible in M phase. Under the light microscope, condensation, alignment and segregation of the chromosomes and cell division itself may be observed during M phase. In addition, different mitotic phases can be distinguished, as shown in Fig. 13.2. 

Although nearly all cellular processes have spatiotemporal patterns and are timed in one way or the other, the outstanding example of a built-in clock is the cell cycle. The wheels and cogs of the clock that time the cell cycle are the cyclins and the cyclin-dependent kinases (Cdks). 

Cyclins are the regulatory moieties of Cdks, the cyclin-dependent kinases. Without cyclins, Cdks are inactive. Each cyclin has a Cdk as parmer and each cyclin/Cdk pair has a different function in the cell cycle. Whereas the concentration of the Cdks is constant, the cellular concentrations of the cyclins vary with the cell-cycle phases, as the name implies. These fluctuations are of regulatory significance, and so are association/ dissociation of cyclin/Cdk complexes. 

Cyclins in higher eukaryotes are classified and divided into eight families, from A to H, based on sequence relationships and the time of appearance in the cell cycle. Although cyclins are a family of diverse proteins, they all have a common region of about 100 amino acids in the C-terminal part. This domain is the cyclin box. 

As cells progress through the cycle, they undergo several discrete transitions. Each transition is an irreversible shift from one level of activities to an other. The most remarkable 

Cell-cycle transitions are driven by the cyclin-dependent kinases 

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Biotin also has a role in regulation of the cell cycle, acting to biotinylate key nuclear proteins. 

Pagano, M., Pepperkok, R., Lukas, J., Baldin, V., Ansorge, W Bartek, J., and Draetta, G. (1993). Regulation of the cell cycle by the cdk2 protein kinase in cultured human fibroblasts. J. Cell Biol. 121 101-111. 

Newport JW, Kirschner MW 1982 Regulation of the cell cycle during early Xenopus development. Cell 37 731—742... 

Cancer results from a disruption of the normal regulation of the cell cycle. When the cycle proceeds without control, cells can divide without order and accumulate genetic defects that can lead to a cancerous tumor. 

Nakayama, K. I., Hatakeyama, S. and Nakayama, K. Regulation of the cell cycle at the Gl—S transition by proteolysis of cydin E and p27Kipl. Biochem Biophys Res Commun 2001, 282, 853-60. 

An overall summary of the regulation of the cell cycle is provided in Figure 20.32. Although the description is oversimplihed it provides a basis for discussion of the mechanisms. 

CDK7/cyclin H were shown to be identical to the CDK-activating protein kinase CAK. CAK is ascribed an important role in the regulation of the cell cycle (see 14.2.1). The fimctional importance of this identity is not yet fully imderstood. 

A more in-depth characterization of the subimits brought surprising results. Some of the polypeptides of TFIIH could be identified as proteins shown in other experiments to participate in repair of DNA damage, as well as in the regulation of the cell cycle (CDK7/Cyclin H, see above). TFIIH itself, or other individual components of TFIIH, thus participate in the following fundamental processes in the cell ... 

CDC2 kinases (representatives of this family are central elements of regulation of the cell cycle, see Chapter 13... 

The MARCKS proteins are a family of proteins that are involved in physiologically important processes such as cell mobility, secretion, membrane transport and in regulation of the cell cycle. All these processes are associated with changes and restructuring of the actin cytoskeleton. The role of converting extracellular signals into changes in the structure of the actin cytoskeleton is attributed to the MARCKS proteins. A... 

Negative regulation of the cell cycle in Gi phase is performed in particular by the inhibitors p21 p27 and pl5 , which are activated by external signals (see above, Fig. 13.10). The inhibitor pl6 also regulates by binding free D type cyclin, which leads to destabilization of cyclin D. 

A number of tumor suppressor genes are known with no direct relationship to the regulation of the cell cycle. Some of the tumor suppressor genes in Table 14.2 are involved in the organization of the cytoskeleton or in cell-cell interactions. 

The Bcl-2 protein was first identified as an oncoprotein coded by a gene affected by translocations of chromosomes 14 and 18 in B cell lymphomas. It was soon shown, however, that the Bcl-2 protein is not involved in regulation of the cell cycle, in contrast to many other oncoproteins, and thus does not fit into the classical oncogene picture. Furthermore, homology was estabhshed with the Ced9 protein of C. elegans, which has an antiapoptotic function in this organism. 

It has been argued that the glycoprotein composition of the cell surface is a determinant in cell behavior,146,149 and it is clear that many properties of cells may be affected by the action of glycosidases on cell-surface glycoproteins. In this respect, changes in their electrophoretic mobility, in the regulation of the cell cycle, and in cell-cell interactions, and the effects on lymphocyte stimulation of cells, their immunogenicity, their interaction with hormones, and their onco-... 

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