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• W2051243152 abstract "One hundred years from now when the dust of the present has long settled and the wizened eye of history levels its gaze at the field of cell cycle regulation, what discovery will it view as the most seminal? With some debate, it is likely to be the discovery of cyclins and the cyclin-dependent kinases (Cdks) they regulate. Cyclins are key regulators of cell cycle transitions whose abundance varies through a cell cycle. Not only did the union of cyclins and Cdks unravel the long-standing mystery of mitotic entry and oocyte maturation and lead to the discovery of the Cdk inhibitors (CKI), but the very nature of cyclin periodicity held within itself the seeds of an equally significant discovery; the role of ubiquitin-mediated proteolysis in cell cycle control. It is now widely understood that cyclin/Cdks work hand-in-hand with ubiquitin-mediated proteolysis to provide the logical framework for cell cycle regulation. Not only are the levels of cyclins regulated by ubiquitination, but so are the levels of a host of other key cell cycle regulators. To duplicate, cells must generally double their contents but precisely solve two specific problems: they must replicate their DNA once and only once per cell cycle, and they must segregate their chromosomes precisely to daughter cells. These are biochemically incompatible processes that are partitioned into temporally distinct cell cycle “states.” The general strategy employed to prevent improper transitions between these states is the use of inhibitory barriers that must be overcome in order for the transition to occur. Often, the same molecule is used both to promote one transition and to inhibit a subsequent transition. For example, in S. cerevisiae Sic1 promotes exit from mitosis by inhibiting Clb/Cdc28 kinases but acts as a barrier to S phase entry that must be overcome. Likewise, S phase cyclins promote initiation of DNA synthesis but prevent the reestablishment of new competent origins thus preventing rereplication, while mitotic cyclins promote entry into mitosis but inhibit mitotic exit. By coupling positive and negative regulators, the cell cycle ensures the maintenance of a single “state” that carries out one defined set of processes at a time. Once the “state” has accomplished its task, events are set in motion that overcome the inhibitory barrier to allow the transition to the next state. The transitions between these states are controlled by ubiquitin-mediated proteolysis. The formation of ubiquitin–protein conjugates requires three components: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a specificity factor (E3) that functions in substrate recognition. Polyubiquitinated proteins are degraded by the 26S proteasome. How and when specific proteins are ubiquitinated is the critical issue concerning the cell cycle, and E3 complexes provide the key to regulated proteolysis. Two E3 complexes were discovered through studies of cell cycle regulation: the cyclosome/anaphase-promoting complex (APC) and the SCF complex. Ubiquitination substrates relevant to the cell cycle fall into two broad categories: those whose destruction is required for cell cycle progression (e.g., Sic1, Pds1, and B-type cyclins), and those whose destruction is not essential but is important for cellular homeostasis (e.g., Cdc6, Cdc20, and G1 cyclins) (Figure 1A). As mentioned above, several proteins have temporally distinct positive and negative roles and their destruction relieves the negative barriers they impose on cell division. In contrast, destruction of strictly positively acting factors such as G1 cyclins is important for resetting the balance of regulatory factors for the next cell cycle such that the timing of subsequent transitions are not inappropriately advanced. SCF. Investigation of the pathway responsible for Cdc34-dependent degradation of Sic1 and G1 cyclins in yeast set the foundation for discovery of the SCF ubiquitin ligase system (19Schwob E Bohm T Mendenhall M.D Nasmyth K Cell. 1994; 79: 233-244Abstract Full Text PDF PubMed Scopus (764) Google Scholar, 1Bai C Sen P Hofmann K Ma L Goebl M Harper J.W Elledge S.J Cell. 1996; 86: 263-274Abstract Full Text Full Text PDF PubMed Scopus (932) Google Scholar, 6Feldman R.M.R Correll C.C Kaplan K.B Deshaies R.J Cell. 1997; 91: 221-230Abstract Full Text Full Text PDF PubMed Scopus (701) Google Scholar, 23Skowyra D Craig K.L Tyers M Elledge S.J Harper J.W Cell. 1997; 91: 209-219Abstract Full Text Full Text PDF PubMed Scopus (1001) Google Scholar). The SCF is the general name for a large collection of modular E3s that are responsible for the ubiquitination of many proteins, including several important for the cell cycle. The SCF is named for three of its core components, Skp1, Cdc53/cullin, and an F box–containing protein (Figure 1B). Skp1 and F box proteins interact through the F box motif. Cdc53 functions as a bridging molecule to bind the Skp1/F box complex to the E2 Cdc34. There are over 400 F box proteins currently in the database, with 20 in S. cerevisiae and over 100 in C. elegans. Many F box proteins also bear obvious protein–protein interaction domains like WD40 or leucine-rich repeats (LRRs). The idea that F box proteins are substrate-specific receptors for ubiquitination substrates came from the finding that the F box proteins Cdc4 and Grr1 are independently involved in Sic1 and Cln ubiquitination, respectively, while other components of the genetic pathway are required for destruction of both of these substrates (1Bai C Sen P Hofmann K Ma L Goebl M Harper J.W Elledge S.J Cell. 1996; 86: 263-274Abstract Full Text Full Text PDF PubMed Scopus (932) Google Scholar; see Table 1). This idea has been borne out by biochemical reconstitution of the Sic1 and Cln1 ubiquitination pathways via SCFCdc4 and SCFGrr1 complexes, respectively (6Feldman R.M.R Correll C.C Kaplan K.B Deshaies R.J Cell. 1997; 91: 221-230Abstract Full Text Full Text PDF PubMed Scopus (701) Google Scholar, 23Skowyra D Craig K.L Tyers M Elledge S.J Harper J.W Cell. 1997; 91: 209-219Abstract Full Text Full Text PDF PubMed Scopus (1001) Google Scholar, 24Skowyra D Koepp D.M Kamura T Conrad M.N Conaway R.C Conaway J.W Elledge S.J Harper J.W Science. 1999; 284: 662-665Crossref PubMed Scopus (350) Google Scholar) (Figure 1B). In both cases, substrate recognition by the F box protein requires that the substrate be phosphorylated. With Sic1, which inhibits Cdks required for S phase entry, this is achieved by Cln/Cdc28-mediated phosphorylation that allows nutrient and cell size information to be coupled to initiation of DNA replication. Association of Grr1 with Clns is mediated by autophosphorylation that allows activation of Cln kinases to eventually turn themselves off to reset the balance for the next G1. F box proteins are also regulated. They are regulated transcriptionally (34Zhang H Kobayashi R Galaktionov K Beach D Cell. 1995; 82: 915-925Abstract Full Text PDF PubMed Scopus (435) Google Scholar, 3Chu S DeRisi J Eisen M Mulholland J Botstein D Brown P.O Herskowitz I Science. 1998; 282: 699-705Crossref PubMed Scopus (1484) Google Scholar) and by proteolysis (35Zhou P Howley P.M Mol. Cell. 1998; 2: 571-580Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar), and the association of F box proteins with Skp1 can also be regulated (14Li F.N Johnston M EMBO J. 1997; 16: 5629-5638Crossref PubMed Scopus (180) Google Scholar).Table 1Substrates of the APC and SCFSCFSubstrateFunctionF Box ProteinCln1aS. cerevisiae;G1 cyclinGrr1Cln2aS. cerevisiae;G1 cyclinGrr1Cln3aS. cerevisiae;G1 cyclin?Clb5aS. cerevisiae;S phase cyclin?Sic1aS. cerevisiae;CDK inhibitorCdc4Far1aS. cerevisiae;CDK inhibitorCdc4Rum1bS. pombe;CDK inhibitorPop1 PLUSPUSSIGN Pop2Swe1aS. cerevisiae;/Wee1cX. laevis;Mitotic inhibitory kinaseMet30/?Cdc6aS. cerevisiae;/Cdc18bS. pombe;DNA replication factorCdc4/?Gcn4aS. cerevisiae;Transcription factor for amino acid regulationCdc4ArmadillodD. melanogaster;/β-catenineH. sapiens;Wnt/Wg-activated transcription factorSlimb/β-TRCPCubitus interruptus (Ci)dD. melanogaster;Hedgehog-activated transcription factorSlimbE2F-1eH. sapiens;Cell cycle transcription factorSkp2Gic2aS. cerevisiae;Polarized bud growth regulatorGrr1IκBeH. sapiens;NF-κB inhibitorβ-TRCPCD4eH. sapiens; (via HIV Vpu)TH cell HIV receptorβ-TRCPPutative SubstratesCyclin D1eH. sapiens;G1 cyclinCyclin EeH. sapiens;G1 cyclinp21eH. sapiens;CDK inhibitorp27eH. sapiens;CDK inhibitorp57eH. sapiens;CDK inhibitorAPCSubstrateFunctionClb2aS. cerevisiae;Mitotic cyclinCyclin AeH. sapiens;,fS. solidissima; andMitotic cyclinCyclin BcX. laevis;,eH. sapiens;,fS. solidissima; andMitotic cyclinCdc20aS. cerevisiae;/p55CdceH. sapiens;APC regulatorCdc5aS. cerevisiae;Mitotic kinase and APC regulatorPds1aS. cerevisiae;/Cut2bS. pombe;Anaphase inhibitorGeminincX. laevis;DNA replication inhibitorAse1aS. cerevisiae;Spindle proteinNIMAgA. nidulans.Mitotic kinaseSuperscripts refer to organism:a S. cerevisiae;b S. pombe;c X. laevis;d D. melanogaster;e H. sapiens;f S. solidissima; andg A. nidulans. Open table in a new tab Superscripts refer to organism: In mammalian cells, the levels of CKI p27 and the G1 cyclins D1 and E are controlled by phosphorylation-dependent ubiquitination (4Elledge S.J Harper J.W Biochim. Biophys. Acta. 1998; 1377: 61-70PubMed Google Scholar and references therein). Given the conservation of regulatory pathways, it is likely that destruction of these and other cell cycle proteins will also involve SCF complexes. Recently is was found that the cell cycle–regulated transcription factor E2F1 binds to SCFSkp2 and is likely to be ubiquitinated by this complex (15Marti A Wirbelaur C Scheffner M Krek W Nat. Cell Biol. 1999; 1: 14-19Crossref PubMed Scopus (279) Google Scholar). The SCF pathway may be the central pathway through which protein kinases control the stability of substrate proteins. It is likely that the SCF will also control the stability of certain nonphosphorylated proteins, although this awaits experimental verification. Most SCF substrates are degraded in the early parts of the cell cycle (Table 1). However, two reports indicate that the SCF is also required for the degradation of a key mitotic regulator, Wee1 (Swe1 in S. cerevisiae). Wee1-like kinases inhibit Cdk function by tyrosine phosphorylation and prevent entry into mitosis. 9Kaiser P Sia R.A.L Bardes E.G.S Lew D.J Reed S.I Genes Dev. 1998; 12: 2587-2597Crossref PubMed Scopus (124) Google Scholar demonstrated that Swe1 binds to the F box protein Met30, and met30 and SCF mutants are defective in Swe1 polyubiquitination, indicating that SCFMet30 controls Swe1 ubiquitination. In addition, 16Michael W.M Newport J Science. 1998; 282: 1886-1889Crossref PubMed Scopus (128) Google Scholar demonstrate that Xenopus Wee1 is degraded in a Cdc34-dependent manner and find that this proteolysis is required for mitotic entry and is coupled to the completion of DNA replication. Genetic evidence exists for a second SCF substrate required for mitosis. Mutants in CDC4 arrest in G1 because they fail to degrade Sic1. However, cdc4sic1 double mutants arrest in G2 suggesting the existence of an unknown inhibitor of mitotic entry (19Schwob E Bohm T Mendenhall M.D Nasmyth K Cell. 1994; 79: 233-244Abstract Full Text PDF PubMed Scopus (764) Google Scholar). Skp1, Cdc53/cullin and F box proteins are not the only essential components of SCF complexes. The recently identified protein Rbx1/Roc1, which contains a Ring-H2 finger domain termed the R box, is also an essential component of the SCF (12Kamura T Koepp D.M Conrad M.N Skowyra D Moreland R.J Iliopoulos O Lane W.S Kaelin W.G Elledge S.J Conaway R.C Harper J.W Conaway J.W Science. 1999; 284: 657-661Crossref PubMed Scopus (643) Google Scholar, 17Ohta T Michel J.J Schottelius A.J Xiong Y Mol. Cell. 1999; 3: 535-541Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar, 24Skowyra D Koepp D.M Kamura T Conrad M.N Conaway R.C Conaway J.W Elledge S.J Harper J.W Science. 1999; 284: 662-665Crossref PubMed Scopus (350) Google Scholar). Mammalian Rbx1/Roc1 was discovered as a protein that bound the von Hippel Lindau (VHL) tumor suppressor complex (12Kamura T Koepp D.M Conrad M.N Skowyra D Moreland R.J Iliopoulos O Lane W.S Kaelin W.G Elledge S.J Conaway R.C Harper J.W Conaway J.W Science. 1999; 284: 657-661Crossref PubMed Scopus (643) Google Scholar) and as a protein that interacts with Cul4a in the two-hybrid system (17Ohta T Michel J.J Schottelius A.J Xiong Y Mol. Cell. 1999; 3: 535-541Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar) and that associates with the SCF (26Tan P Fuchs S.Y Chen A Wu K Gomez C Ronai Z Pan Z.-Q Mol. Cell. 1999; 3: 527-533Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar). The VHL complex also contains a Skp1 homolog, Elongin C, and a Cdc53 homolog, Cul2, and is therefore structurally analogous to SCF complexes (Figure 1C). VHL binds Elongin B/C through a short BC box motif related to the F box (25Stebbins C.E Kaelin W.G Pavletich N.P Science. 1999; 284: 455-461Crossref PubMed Scopus (657) Google Scholar). Additional BC box–containing proteins can bind to Elongin B/C in place of VHL and may confer different functions upon the complex, much like F box proteins do to the SCF (11Kamura T Sato S Haque D Liu L Kaelin W.G Conaway R.C Conaway J.W Genes Dev. 1998; 12: 3872-3881Crossref PubMed Scopus (487) Google Scholar). In yeast, Rbx1/Roc1 is essential for viability and is required for Sic1 and Cln ubiquitination in vitro (12Kamura T Koepp D.M Conrad M.N Skowyra D Moreland R.J Iliopoulos O Lane W.S Kaelin W.G Elledge S.J Conaway R.C Harper J.W Conaway J.W Science. 1999; 284: 657-661Crossref PubMed Scopus (643) Google Scholar, 17Ohta T Michel J.J Schottelius A.J Xiong Y Mol. Cell. 1999; 3: 535-541Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar, 24Skowyra D Koepp D.M Kamura T Conrad M.N Conaway R.C Conaway J.W Elledge S.J Harper J.W Science. 1999; 284: 662-665Crossref PubMed Scopus (350) Google Scholar). Consistent with this, Rbx1/Roc1 greatly enhances the activity of insect cell–derived SCFCdc4 complexes toward Sic1 (12Kamura T Koepp D.M Conrad M.N Skowyra D Moreland R.J Iliopoulos O Lane W.S Kaelin W.G Elledge S.J Conaway R.C Harper J.W Conaway J.W Science. 1999; 284: 657-661Crossref PubMed Scopus (643) Google Scholar) and allows reconstitution of phosphorylation-dependent Cln1 ubiquitination by recombinant SCFGrr1 complexes (24Skowyra D Koepp D.M Kamura T Conrad M.N Conaway R.C Conaway J.W Elledge S.J Harper J.W Science. 1999; 284: 662-665Crossref PubMed Scopus (350) Google Scholar). Rbx1/Roc1 is highly conserved and it is therefore likely that insect cell–derived Rbx1/Roc1 is responsible for the previously observed activity of SCFCdc4 toward Sic1 (6Feldman R.M.R Correll C.C Kaplan K.B Deshaies R.J Cell. 1997; 91: 221-230Abstract Full Text Full Text PDF PubMed Scopus (701) Google Scholar, 23Skowyra D Craig K.L Tyers M Elledge S.J Harper J.W Cell. 1997; 91: 209-219Abstract Full Text Full Text PDF PubMed Scopus (1001) Google Scholar). The ability of Rbx1/Roc1 to activate the SCF appears to reflect its recruitment of Cdc34 into the SCF complex (24Skowyra D Koepp D.M Kamura T Conrad M.N Conaway R.C Conaway J.W Elledge S.J Harper J.W Science. 1999; 284: 662-665Crossref PubMed Scopus (350) Google Scholar). Furthermore, association of Cdc34 with the Rbx1/SCF complex greatly stimulates its autopolyubiquitination activity, suggesting that the complex is an allosteric activator of Cdc34. The APC also contains an Rbx1/Roc1-related protein, Apc11, which is required for Clb2 ubiquitination in vitro (33Zachariae W Shevchenko A Andrews P.D Ciosk R Galova M Stark M.J Mann M Nasmyth K Science. 1998; 279 (b): 1216-1219Crossref PubMed Scopus (293) Google Scholar). The finding that mammalian cullin Apc2 interacts with Apc11 in cotransfection experiments (17Ohta T Michel J.J Schottelius A.J Xiong Y Mol. Cell. 1999; 3: 535-541Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar) strengthens the mechanistic parallels between the APC and the SCF and suggests that the role of Apc11 involves E2 recruitment. Since Rbx1/Roc1 is a component of multiple cullin complexes, including the VHL complex, it seems likely that many cullin complexes will be involved in transfer of ubiquitin or ubiquitin-like proteins. In addition to Rbx1/Roc1 and Apc11, yeast contain several R box proteins, three of which (Hrd1, Rad18, and Ubr1) are also involved in ubiquitination pathways. It has been proposed that E3 complexes fall into two basic categories, the SCF-like complexes such as SCF, VHL-Elongin, and the APC, which utilize R box proteins, and the HECT domain proteins, which so far have not been linked to R box proteins (24Skowyra D Koepp D.M Kamura T Conrad M.N Conaway R.C Conaway J.W Elledge S.J Harper J.W Science. 1999; 284: 662-665Crossref PubMed Scopus (350) Google Scholar). APC. In mitosis, two events are subject to proteolytic control, sister chromosome separation and exit from telophase into G1. These ubiquitin-mediated proteolytic events depend upon the APC, an E3 composed of 12 subunits in budding yeast (32Zachariae W Schwab M Nasmyth K Seufert W Science. 1998; 282 (a): 1721-1724Crossref PubMed Scopus (432) Google Scholar) and at least 10 subunits in mammals and Xenopus (31Yu H Peters J.M King R.W Page A.M Hieter P Kirschner M.W Science. 1998; 279: 1219-1222Crossref PubMed Scopus (202) Google Scholar). A central question has been how this E3 can differentially regulate the timing of substrate ubiquitination. Destruction of many APC targets requires the presence of a conserved 9-residue motif called the “destruction box.” In Drosophila, expression of destruction box–deficient cyclin A leads to a metaphase delay while deletion of destruction boxes in cyclin B and B3 lead to early anaphase and late anaphase arrest, respectively (22Sigrist S Jacobs H Stratmann R Lehner C.F EMBO J. 1995; 14: 4827-4838Crossref PubMed Scopus (253) Google Scholar). Similarly, deletion of the destruction boxes in negative regulators of sister chromosome separation, Pds1 in budding yeast and Cut2 in S. pombe, blocks cells in metaphase (30Yanagida M Trends Cell Biol. 1998; 8: 144-149Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Progression from metaphase to anaphase to mitoic exit is controlled by the sequential degradation of inhibitors by the APC. How does a cell know when and which substrate to ubiquitinate? Substrate specificity is accomplished in part by the regulated association of the APC with two classes of WD40 repeat–containing coactivator proteins, Cdc20/fizzy and Cdh1/Hct1/fizzy-related (18Schwab M Lutum A.S Seufert W Cell. 1997; 90: 683-693Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar, 27Visintin R Prinz S Amon A Science. 1997; 278: 460-463Crossref PubMed Scopus (691) Google Scholar, 5Fang G Yu H Kirschner M.W Mol. Cell. 1998; 2: 163-171Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar, 13Kramer E.R Gieffers C Holzl G Hengstschlager M Peters J.M Curr. Biol. 1998; 8: 1207-1210Abstract Full Text Full Text PDF PubMed Google Scholar). In budding yeast, Cdc20 controls ubiquitination of Pds1 at the metaphase-to-anaphase transition whereas its homolog Cdh1/Hct1 controls mitotic cyclin destruction and mitotic exit (27Visintin R Prinz S Amon A Science. 1997; 278: 460-463Crossref PubMed Scopus (691) Google Scholar, 18Schwab M Lutum A.S Seufert W Cell. 1997; 90: 683-693Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar, 21Sigrist S.J Lehner C.F Cell. 1997; 90: 671-681Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar). Cdc20 is expressed during G2 and binds the APC during metaphase. Association of Cdc20 with the APC allows ubiquitination of Pds1, thereby removing the block to anaphase, and expression of Cdc20 prior to mitosis can cause premature degradation of Pds1 but not mitotic cyclins (27Visintin R Prinz S Amon A Science. 1997; 278: 460-463Crossref PubMed Scopus (691) Google Scholar). Several substrates may be ubiquitinated by the same form of the APC, but in a defined order. How this works is not clear. One possibility is that substrates of the APC are themselves specific inhibitors of the destruction of other substrates. Evidence supporting this model comes from Drosophila in which destruction of cyclin A is required for destruction of cyclin B, and destruction of cyclin B is required for the destruction of cyclin B3, whose destruction is required for mitotic exit (22Sigrist S Jacobs H Stratmann R Lehner C.F EMBO J. 1995; 14: 4827-4838Crossref PubMed Scopus (253) Google Scholar). It is not known whether Cdc20 or Cdh1 binds directly to substrates and whether, like their WD40 F box counterparts, substrate phosphorylation will play a role in substrate selection. Theoretically, phosphorylation could also control inhibitor binding to Cdc20 and Cdh1. The spindle assembly checkpoint controlled by the MAD/BUB genes prevents anaphase in part by regulated association of Mad2 with Cdc20 (Figure 1D). Whether this process involves phosphorylation remains to be determined although there are several protein kinases in the Mad/Bub pathway. In contrast to Cdc20, Cdh1 is present constitutively but binds the APC only during mitotic exit and G1, points in the cell cycle where mitotic cyclins are unstable. Cdh1 overexpression causes degradation of ectopically expressed Clb2, and its homolog fizzy-related is required for destruction of mitotic cyclins in Drosophila. A recent flurry of papers has clarified how Cdh1 activity is regulated (28Visintin R Craig K Hwang E.S Prinz S Tyers M Amon A Mol. Cell. 1998; 2: 709-718Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar, 32Zachariae W Schwab M Nasmyth K Seufert W Science. 1998; 282 (a): 1721-1724Crossref PubMed Scopus (432) Google Scholar, 8Jaspersen S.L Charles J.F Morgan D.O Curr. Biol. 1999; 9: 227-236Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar). Not unexpectedly, Cdh1 regulation underlies the inverse relationship between Cdk activity and activation of B-type cyclin destruction. During most of the cell cycle, Cdh1 is inhibited by Cdk phosphorylation (Figure 1D). Cdh1 is activated by the phosphatase Cdc14, which functions in three parallel processes that ensure precipitous destruction of B-type cyclins and mitotic exit. Cdc14 acts during telophase to dephosphorylate not only Cdh1, but also Swi5, a transcription factor held dormant in the cytoplasm by Cdk phosphorylation. Swi5 dephosphorylation activates Sic1 transcription. Cdc14 also protects Sic1 from SCFCdc4 degradation by dephosphorylating Sic1. Increased levels of Sic1 block Clb/Cdc28 activity, which helps tip the balance of kinase and phosphatase activity toward Cdh1 dephosphorylation and mitotic exit (Figure 1D). Regulated access of Cdc14 to its substrates is responsible for setting up the timing of mitotic exit (20Shou W Seol J.H Shevchenko A Baskerville C Moazed D Chen Z.W.S Jang J Shevchenko A Chabonneau H Deshaies R.J Cell. 1999; 97: 233-244Abstract Full Text Full Text PDF PubMed Scopus (583) Google Scholar, 29Visintin R Hwang E.S Amon A Nature. 1999; 398: 818-823Crossref PubMed Scopus (474) Google Scholar). During G1 through early mitosis, Cdc14 is in the nucleolus. As sister chromosomes separate, Cdc14 is released from the nucleolus and spreads throughout the nucleus and into the cytoplasm where it finds key substrates. Cdc14 is sequestered in the nucleolus through association with Cfi1/Net1, which shows constitutive nucleolar localization. Deletion of CFI1/NET1 leads to dispersion of Cdc14 throughout the cell. Mitotic exit requires several genes (7Jaspersen S.L Charles J.F Tinker-Kulberg R.L Morgan D.O Mol. Biol. Cell. 1998; 9: 2803-2817Crossref PubMed Scopus (257) Google Scholar), including TEM1, CDC15, DBF2, DBF20, LTE1, and CDC5. Deletion of CFI1/NET1 rescues temperature-sensitive tem1, cdc5, cdc15, and dbf2 mutants, suggesting that the mitotic exit role of these proteins is to release Cdc14 from Cfi1/Net1. Given that several of these genes encode protein kinases, phosphorylation of Cdc14, Cfi1/Net1, or both is a likely mechanism for dissociation. A key unresolved issue is the nature of the CDC20-dependent signal that activates the mitotic exit pathway, for this ensures that anaphase preceeds mitotic exit. As is readily apparent, proteolysis plays a tremendously important and varied role in cell cycle regulation. While the SCF and APC are key regulators, other proteolytic systems may also contribute to cell cycle control. A well-documented case is the stabilization of p53 in response to DNA damage. In addition, a novel proteolyic system cabable of cleaving cyclin A was recently found to be activated by the presence of the CKI p27 in cell extracts (2Bastians H Townsley F.M Ruderman J.V Proc. Natl. Acad. Sci. USA. 1998; 95: 15374-15381Crossref PubMed Scopus (27) Google Scholar). Furthermore, the regulation of protein stability at the proteolytic step rather than the ubiquitination step is an interesting and unexplored avenue for cell cycle control. A possible example of this may come from the recent observation that the Cdk subunit Cks1 (Suc1 in S. pombe) associates with the proteasome and may regulate it (10Kaiser P Moncollin V Clarke D.J Watson M.H Bertolaet B.L Reed S.I Bailly E Genes Dev. 1999; in pressGoogle Scholar). The significance of these new discoveries is not yet clear but they are certain to keep cell cycle research on the cutting edge." @default.
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• W2051243152 title "How the Cyclin Became a Cyclin" @default.
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