Regulation of the Cell Cycle by Proteolysis

Examples of proteins that are specifically phosphorylated during the cell cycle are the lamins. Hyperphosphorylation of the lamins leads to disintegration of the nuclear lamina. Myosin in actin-myosin filaments is also specifically phosphorylated during mitosis. Other M-phase-specific phosphorylations occur at transcription factor TFIIIB, leading to inhibition of transcription by RNA polymerase III. Phosphorylation of TAP proteins (see 1.4.2.3) is also involved in general inhibition of banscription. 

The following have a positive effect on activity of CDKs  

These regulation mechanisms caimot be considered in isolation. Rather, it must be assumed that the individual mechanisms cooperate, and demonsbate mutual regulation and that feedback mechanisms are built in. All control elements can be activated, in principle, by external signals, resulting in a complex network of cell cycle control with many entry and exit points. The following sections are thus highly incomplete and only describe the elements that have been experimentally well proven. 

The ordered coinse of the cell cycle is ensured by two processes in particular  

Both processes, the protein kinase regulatory network of CDKs and targeted proteolysis, are linked to one another and work in mutual dependence. For a review on the control of the cell cycle by targeted proteolysis see King et al, (1996) and Hersko (1997). 

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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. 

The 26S proteasome also degrades non-ubiquitylated proteins [71]. The short-lived enzyme ornithine decarboxylase (ODC) and the cell-cycle regulator p21Cip provide well documented examples of ubiquitin-independent proteolysis by the 26S en-... 

The inhibitor p27 is regulated at the post-translational level. p27 4 exists in an inactive, masked form in proliferating cells. It may be converted into the active form by an as yet unknown mechanism so that the cell cycle can be halted. Activation of p27 may be triggered by treatment of cells with TGPp, by cell-cell contact and by an increase in the cAMP concentration. Purthermore, p27 is subject to specific, ubiquitin-mediated proteolysis (see below). 

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.

Figure 4. Ubiquitin-mediated proteolysis regulates the onset and demise of Cdk activity during the cell division cycle. The Anaphase Promoting Complex/Cyclosome (APC/C) is active from the onset of anaphase until the end of G1 phase, during which it targets mitotic cyclins (Clbs) and other proteins such as Pdsl. The SCF complex is constitutively active but only targets Sicl and other substrates once they have been specifically phosphorylated by G1 cyclin (Cln)-Cdk (Cdc28) activity. See text for details.

Ubiquitin-dependent proteolysis is as important for the regulation of cellular processes as for the elimination of defective proteins. Many proteins required at only one stage of the eukaryotic cell cycle are rapidly degraded by the ubiquitin-dependent pathway after completing their function. The same pathway also processes and presents class I MHC antigens (see Fig. 5-22). Ubiquitin-dependent destruction of cyclinis critical to cell-cycle regulation (see Fig. 12-44). The E2 and E3 components of the ubiquitination cascade pathway... 

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