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Chapter category: Cell Cycle

Activating Phosphorylation of Cyclin-Dependent Kinases in Budding Yeast

Chapter authors:
Philipp Kaldis, Vasiliki Tsakraklides, Karen E. Ross, Edward Winter

The eukaryotic cell division cycle is controlled via the sequential activation and inactivation of cyclin-dependent protein kinases (cdks). In the budding yeast Saccharomyces cerevisiae, Cdc28p is the only CDK involved in regulating the cell cycle, while in higher eukaryotes, multiple CDKs (CDC2 [CDK1], CDK2, CDK4, and CDK6) control cell cycle progression. Cdk substrates are assumed to be key players in most major cell cycle events. To ensure the proper timing and coordination of cell cycle events, intracellular and extracellular signals modulate CDK activities through a variety of mechanisms, including association with regulatory subunits (cyclins, inhibitors, and assembly factors), subcellular localization, transcriptional regulation, selective proteolysis, and reversible protein phosphorylation.^1-7

Binding of cyclins to CDKs is required for kinase activity. Cyclins also likely contribute to the substrate specificity^8,9 and to the subcellular localization of CDKs.^10-14 Furthermore, cyclin binding leads to multiple phosphorylations on the CDK in Xenopus egg extracts.^15,16 Cyclins are synthesized, and degraded periodically during the cell cycle.^1,4,17,18 The synthesis of cyclins is mostly controlled at the level of transcription¹⁹ and they are degraded by ubiquitin-mediated proteolysis. Cyclins are recognized by the ubiquitin-protein ligases APC (anaphase-promoting complex) or SCF (Skp1p-Cdc53p/cullin-F-box protein), polyubiquitinated, and destroyed by the 26S proteasome.^20,21 In the budding yeast, nine cyclins form complexes with Cdc28p: three G1 cyclins (Cln1p to Cln3p) and six B-type cyclins (Clb1p to Clb6p). In the G1 phase, Cln1-3p regulate cell cycle events such as "Start" (equivalent of restriction point in mammalian cells),^22,23 the repression of pheromone-induced transcription, and meiosis in diploid cells.^24,25 Btype cyclins are expressed in three successive waves from Start to mitosis and regulate most events during the cell cycle (reviewed in 26).

In budding yeast, there are two Cdc28p inhibitors (CKIs): Far1p and Sic1p. Far1p, which is required for pheromone-induced cell cycle arrest,²⁷ inhibits the kinase activities of Cln1p-Cdc28p, Cln2p-Cdc28p, and Cln3p-Cdc28p,^22,28,29 but it is incapable of reducing Clb5p or Clb2p associated Cdc28p activities.²⁹ In contrast to Far1p, Sic1p is a specific inhibitor of B-type cyclin-Cdc28p complexes.^30,31 Sic1p has two functions: in G1, it prevents premature S-phase entry before bud initiation and spindle pole body (SPD) duplication.³¹ At the end of mitosis, it promotes mitotic exit by inhibiting Clb-Cdc28p activity.^32,33 It should be noted that there is no apparent sequence homology between yeast CKIs and their mammalian counterparts. Mammalian CKIs are classified in two groups: the CIP/KIP family consisting of p21^CIP1/WAF1,^34-36 p27^KIP1,^37-39 and p57^{KIP2 40,41} which inhibit all CDKs; and the INK4 family including p15^INK4b,⁴² p16^INK4a,⁴³ p18^{INK4c 44} and p19^{INK4d 45,46} that are specific CDK4/CDK6 inhibitors.

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