Cell Cycle Regulation

Association with small inhibitory proteins is a universal mechanism of CDK regulation (Sherr and Roberts, 1999), though the CKIs (Cyclin-dependent Kinase Inhibitors) involved are highly divergent between yeasts and metazoans. Three different proteins, p21 Cip1 , p27 Kip1  and p57 Kip2 , form the "CDK inhibitory Protein/Kinase Inhibitor protein" (Cip/Kip) family in mammals. The  C. elegans  genome encodes two members of this family: CKI-1 and CKI-2 (Feng et al., 1999; Hong et al., 1998). Although both predicted proteins are similarly close in amino-acid sequence to p21 Cip1  and p27 Kip1 , only CKI-1 appears to act generally in cell-cycle control (Boxem and van den Heuvel, 2001; Feng et al., 1999; Fukuyama et al., 2003; Hong et al., 1998). Several results have shown that CKI-1 acts to promote cell-cycle arrest throughout development, analogous to p27 Kip1  in mammals and  Dacapo  in flies. A...

The  C. elegans  genome encodes multiple members of the cyclin-dependent kinase (CDK) family. At least two CDKs, CDK-1 and CDK-4, are essential for cell-cycle progression (Boxem et al., 1999; Boxem and van den Heuvel, 2001; Park and Krause, 1999). These CDKs act at distinct times in the cell cycle and use specific cyclin partners, similar to their mammalian orthologs (Table 1). CDK-1, previously known as NCC-1 for  n ematode  c ell  c ycle, was identified based on its close similarity to the prototypical yeast CDK (Mori et al., 1994). In contrast to yeast, but similar to mammalian Cdk1,  cdk-1 / (ncc-1)  is specifically required for G 2 /M progression and not for G 1  or S phase (Boxem et al., 1999). Maternal  cdk-1  product suffices for embryogenesis, and candidate null mutant animals arrest cell division during L1 development. Several observations indicate that the post-embryonic precursor cells in these mu...

The collective results from studies in various eukaryotes have demonstrated that progression through the cell-division cycle is driven by activation and inactivation of cyclin-dependent kinases (CDKs), which trigger the transition to subsequent phases of the cycle. CDKs are small serine/threonine protein kinases that require association with a cyclin subunit for their activation. In yeast, a single CDK (p34 CDC28  in  Saccharomyces cerevisiae  and p34 cdc2  in  Schizosaccharomyces pombe ) acts with different cyclins to promote progression through G 1 , S and G 2 /M. Metazoans, including  C. elegans , use not only a variety of cyclins but also multiple catalytic subunits (Figure 1C). Many levels of regulation impinge upon the CDKs to impose tight control over cell-cycle progression. Such regulation involves controlled expression and destruction of cyclins, activating and inhibitory phosphorylation and dephosphorylation of the CDKs, and expression and des...

A Cdks is an enzyme that adds negatively charged phosphate groups to other molecules in a process called phosphorylation. Through phosphorylation, Cdks signal the cell that it is ready to pass into the next stage of the cell cycle. As their name suggests, Cyclin-Dependent Protein Kinases are dependent on cyclins, another class of regulatory proteins. Cyclins bind to Cdks, activating the Cdks to phosphorylate other molecules. Cyclins Cyclins are named such because they undergo a constant cycle of synthesis and degradation during cell division. When cyclins are synthesized, they act as an activating protein and bind to Cdks forming a cyclin-Cdk complex. This complex then acts as a signal to the cell to pass to the next cell cycle phase. Eventually, the cyclin degrades, deactivating the Cdk, thus signaling exit from a particular phase. There are two classes of cyclins: mitotic cyclins and G1 cyclins. In this section, we will review the biological regulators of the cell cycle. Cont...

Cdks, cyclins, and the APC/C are direct regulators of cell cycle transitions, but they aren’t always in the driver’s seat. Instead, they respond to cues from inside and outside the cell. These cues influence activity of the core regulators to determine whether the cell moves forward in the cell cycle. Positive cues, like growth factors, typically increase activity of Cdks and cyclins, while negative ones, like DNA damage, typically decrease or block activity. As an example, let's examine how DNA damage halts the cell cycle in G _1 ​ 1 ​ ​ start subscript, 1, end subscript . DNA damage can, and will, happen in many cells of the body during a person’s lifetime (for example, due to UV rays from the sun). Cells must be able to deal with this damage, fixing it if possible and preventing cell division if not. Key to the DNA damage response is a protein called p53, a famous tumor suppressor often described as “the guardian of the genome.”  ^{10} ​ 1 0 ​ ​ start superscript, 10, end...

In addition to driving the events of M phase, MPF also triggers its own destruction by activating the  anaphase-promoting complex/cyclosome  ( APC/C ), a protein complex that causes M cyclins to be destroyed starting in anaphase. The destruction of M cyclins pushes the cell out of mitosis, allowing the new daughter cells to enter G _1 ​ 1 ​ ​ start subscript, 1, end subscript . The APC/C also causes destruction of the proteins that hold the sister chromatids together, allowing them to separate in anaphase and move to opposite poles of the cell. How does the APC/C do its job? Like a Cdk, the APC/C is an enzyme, but it has different type of function than a Cdk. Rather than attaching a phosphate group to its targets, it adds a small protein tag called  ubiquitin  ( Ub ). When a target is tagged with ubiquitin, it is sent to the  proteasome , which can be thought of as the recycle bin of the cell, and destroyed. For example, the APC/C attaches a ubiquitin tag...