Cell cycle kinases, regulation

Longshaw, V.M. et al. (2004) Nuclear translocation of the Hsp70/Hsp90 organizing protein mSTIl is regulated by cell cycle kinases./. Cell Sci. 117, 701-710. 

As might be expected from other mechanisms of regulation described in this text, phosphorylation and dephosphorylation of key proteins is the main mechanism for regulating the cycle, i.e. reversible phosphorylation, also known as interconversion cycles (discussed in Chapter 3). In the cell cycle, several of these interconversion cycles play a role in control at the checkpoints. Two important terms must be appreciated to help understand the mechanism of regulation of the cycle the phosphorylation of proteins is catalysed by specific protein kinases, known as cell-division kinases (cdck) or cell cycle kinases (cck) and these enzymes are activated by specific proteins, known as cyclins. 

Figure 20.31 The principle of interconversion cycles in regulation of protein activity or changes in protein concentration as exemplified by translation/proteolysis or protein kinase/protein phosphatase. They result in very marked relative changes in regulator concentration or enzyme activity. The significance of the relative changes (or sensitivity in regulation) is discussed in Chapter 3. The principle of regulation by covalent modihcation is also described in Chapter 3. The modifications in cyclin concentration are achieved via translation and proteolysis, which, in effect, is an interconversion cycle. For the enzyme, they are achieved via phosphorylation and dephosphorylation reactions. In both cases, the relative change in concentration/activity by the covalent modification is enormous. This ensures, for example, that a sufficient increase in cyclin can occur so that an inactive cell cycle kinase can be converted to an active cell cycle kinase, or that a cell cycle kinase can be completely inactivated. Appreciation of the common principles in biochemistry helps in the understanding of what otherwise can appear to be complex phenomena.

Mechanism of regulation of cell cycle kinases and activation of checkpoints... 

Figure 20.32 A hypothesis for regulation of cydin-dependent cell cycle kinase by changes in the concentration of a cyclin and how...

Figure 21.17 Overview of the regulation of the genes that express three proteins essential for DNA synthesis. The Rb gene expresses Rb which inactivates the transcription factor by forming a complex. Phosphorylation of the Rb protein by a cell cycle kinase causes dissociation of complex and release of transcription factor, which is now active and stimulates expression of the three genes. THFR, tetra hydrofolate reductase. See chapter 20 for details of the actions of cyclins, DNA polymerase and THFR in the cell cycle.

The progression of the cell cycle is regulated by interconversion processes, in each phase, special Ser/Thr-specific protein kinases are formed, which are known as cyclin-depen-dent kinases (CDKs). This term is used because they have to bind an activator protein (cyclin) in order to become active. At each control point in the cycle, specific CDKs associate with equally phase-specific cyclins. if there are no problems (e.g., DNA damage), the CDK-cyclin complex is activated by phosphorylation and/or dephosphorylation. The activated complex in turn phosphorylates transcription factors, which finally lead to the formation of the proteins that are required in the cell cycle phase concerned (enzymes, cytoskeleton components, other CDKs, and cyclins). The activity of the CDK-cyclin complex is then terminated again by proteolytic cyclin degradation. 

S. Chakravarty, S. Dugar (2002). Inhibitors of p38a MAL kinase. A m<. Rep. Med. Chem. 37 111. Y. Dai, S. Grant (2003). Cyclin-dependent kinase inhibitors. Curr. Opin. Pharmacol. 3 362-370. S. D. Kimball, K. R. Webster (2001). Cell cycle kinases and checkpoint regulation in cancer. Annu. Rep. Med. Chem. 36 139. 

A biochemical system is at the center of the cell cycle, of which the most important players are Ser/Thr-specific protein kinases and regulatory proteins associated with these. The activity of this central cell cycle apparatus regulates processes downstream that help to carry out the many phase-specific biochemical reactions of the cell cycle in a defined order. 

Progression through the cell cycle is regulated by the cyclin-dependent protein kinases (CDKs), which act at specific points in the cycle, phosphorylating key proteins and modulating their activities. The catalytic subunit of CDKs is inactive unless associated with the regulatory cyclin subunit. 

Hg. 6.1 Cell cycle and regulation of cell cycle progression by cyclin-dependent kinases [3]. Cl, Capi phase between M and S phases S, DNA synthesis phase G2 gap 2 phase between S and M phases and M, mitosis phase. 

Jazayeri A, Ealck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP. ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat. Cell. Biol. 2006 8 37 5. Kaneko YS, Watanabe N, Morisaki H, Akita H, Fujimoto A, Tominaga K, Terasawa M, Tachibana A, Ikeda K, Nakanishi M. Cell-cycle-dependent and ATM-independent expression of human Chkl kinase. Oncogene 1999 18 3673-3681. 

The cell cycle is regulated by specific proteins CDKs, which are serine/threonine protein kinases, and the cyclins, which are regulatory proteins that bind to the CDKs. 

The last part of this account will be devoted to protein kinases and protein phosphatases and some recent results we have obtained for them. Protein kinases and phosphatases are signaling biomolecules that control the level of phosphorylation and dephosphorylation of tyrosine, serine or threonine residues in other proteins, and by this means regulate a variety of fundamental cellular processes including cell growth and proliferation, cell cycle and cytoskeletal integrity. 

Conformational changes in a protein kinase are important for cell cycle regulation... 

Cell Cycle Control. Figure 1 Cell cycle regulation by Cyclin dependent kinases (CDKs). Different cyclins bound to different CDKs promote the transition from one cell cycle phase into another. CDK-dependent phosphorylation of Rb is required to release active E2F transcription factors, which promotes entry into S phase. 

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