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Snapshot: Cell-Cycle Regulators I David O SnapShot: Cell-Cycle Regulators I David O. Morgan University of California, San Francisco, CA 94143, USA S. cerevisiae S. pombe D. melanogaster X. laevis H. sapiens Function Phase (Budding Yeast) (Fission Yeast) (Fruit Fly) (Clawed Toad) (Human) Cyclin- Protein kinase Cdk1 (Cdc28): all Cdk1 (Cdc2): all Cdk1 (Cdc2): Cdk1 (Cdc2): Cdk1 (Cdc2): dependent catalytic stages stages M phase M phase M phase kinases (Cdks) subunit, Cdk2 (Cdc2c): Cdk2: G1/S, S Cdk2: G1/S, inactive unless G1/S, S, possibly S bound to M cyclin and phosphorylated Cdk4: G1, growth Cdk4: G1 Cdk4, Cdk6: by CAK regulation G1 Cyclins Stage-specifi c G1 Cln3 Puc1? Cyclin D Cyclin D Cyclin D1, activators of (binds Cdk1) (binds Cdk1) (binds Cdk4) (binds Cdk4) D2, D3 Cdk catalytic (bind Cdk4 or subunits Cdk6) G1/S Cln1, 2 Puc1, Cig1? Cyclin E Cyclin E Cyclin E (bind Cdk1) (bind Cdk1) (binds Cdk2) (binds Cdk2) (binds Cdk2) S Clb5, 6 Cig2, Cig1? Cyclin A Cyclin A1, A2 Cyclin A1, A2 (bind Cdk1) (bind Cdk1) (binds Cdk1) (bind Cdk2, (bind Cdk2, Cdk1) Cdk1) M Clb1, 2, 3, 4 Cdc13 Cyclin B, B3 Cyclin B1, B2 Cyclin B1, B2 (bind Cdk1) (binds Cdk1) (bind Cdk1) (bind Cdk1) (bind Cdk1) Cdk-activating Phosphorylates monomeric Cak1 (Civ1) Csk1 kinase (CAK) Cdk subunit at Cdk- Mcs6 Cdk7 Cdk7 Cdk7 single threonine related (+ cyclin Mcs2) (+ cyclin H) (+ cyclin H) (+ cyclin H) in active site; required for full Cdk activity APC Stage-specifi c Anaphase Cdc20 Slp1 Fizzy (Fzy) Cdc20 (anaphase- activators of onset (p55CDC, promoting multisubunit Fizzy) complex) APC core Late M, G1 Cdh1 (Hct1) Srw1 (Ste9) Fizzy-related (Fzr, Cdh1 (Fizzy- ubiquitin ligase- Rap) related) activating subunits Meiosis Ama1 Mfr1 Cortex ? 764 Cell 135, November 14, 2008 ©2008 Elsevier Inc. DOI 10.1016/j.cell.2008.10.039 See online version for legend and references. SnapShot: Cell-Cycle Regulators I David O. Morgan University of California, San Francisco, CA 94143, USA Progression through the eukaryotic cell cycle is governed by a complex regulatory system whose central component is the cyclin-dependent kinase (Cdk). The yeast cell cycle is controlled by a single Cdk called Cdk1, whereas animal cells employ a small family of Cdks, with Cdk1 and Cdk2 being the key players. Cdk activation requires as- sociation with a cyclin subunit, as well as phosphorylation of the Cdk subunit by the Cdk-activating kinase (CAK). The three major classes of cyclins, called G1/S, S, and M cyclins, oscillate in the cell cycle to generate a series of cyclin-Cdk complexes that are abruptly switched on at specific cell-cycle transitions. These cyclin-Cdks phosphorylate numerous substrates that trigger chromosome duplication in S phase and mitotic spindle assembly and other preparations for chomosome segregation in mitosis. The G1 cyclins do not exhibit dramatic oscillations in proliferating cells but form constitutively active G1-Cdk complexes that help initiate the activation of G1/S- and S-Cdks. G1-Cdk activity, and thus cell-cycle entry, is responsive to cell size or mitogenic signals from outside the cell. An additional key component of the cell-cycle control system is a multisubunit ubiquitin-protein ligase called the anaphase-promoting complex or cyclosome (APC or APC/C). The APC core contains 12 to 13 subunits (not listed here), most of which have been conserved in eukaryotic evolution. APC activity requires association with activator subunits that recruit substrates to the APC. The APC is activated in early mitosis by association with Cdc20, leading to the ubiquitination and destruction of two major substrates: (1) securin, the destruction of which unleashes sister-chromatid separation; and (2) S- and M-cyclins, the destruction of which inactivates Cdks, allowing dephosphorylation of Cdk substrates and the completion of M phase. After anaphase, Cdc20 is replaced by Cdh1, which maintains APC activity in late mitosis and through the following G1 to the start of the next cell cycle. Abbreviations Cdk, cyclin-dependent kinase; CAK, Cdk-activating kinase; APC, anaphase-promoting complex or cyclosome. REFERENCES Morgan, D.O. (2007). The Cell Cycle: Principles of Control (London: New Science Press). Peters, J.M. (2006). The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat. Rev. Mol. Cell Biol. 7, 644–656. 764.e1 Cell 135, November 14, 2008 ©2008 Elsevier Inc. DOI 10.1016/j.cell.2008.10.040.
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