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• W2023259159 abstract "Ubiquitin-dependent proteolysis of specific target proteins is required for several important steps during the cell cycle. Degradation of such proteins is strictly cell cycle-regulated and triggered by two large ubiquitin ligases, termed anaphase-promoting complex (APC) and Skp1/Cullin/F-box complex (SCF). Here we show that yeast Ran-binding protein 1 (Yrb1p), a predominantly cytoplasmic protein implicated in nucleocytoplasmic transport, is required for cell cycle regulated protein degradation. Depletion of Yrb1p results in the accumulation of unbudded G1cells and of cells arrested in mitosis implying a function of Yrb1p in the G1/S transition and in the progression through mitosis. Temperature-sensitive yrb1-51 mutants are defective in APC-mediated degradation of the anaphase inhibitor protein Pds1p and in degradation of the cyclin-dependent kinase inhibitor Sic1p, a target of SCF. Thus, Yrb1p is crucial for efficient APC- and SCF-mediated proteolysis of important cell cycle regulatory proteins. We have identified the UBS1 gene as a multicopy suppressor of yrb1-51 mutants. Ubs1p is a nuclear protein, and its deletion is synthetic lethal with a yrb1-51 mutation. Interestingly, UBS1 was previously identified as a multicopy suppressor of cdc34-2 mutants, which are defective in SCF activity. We suggest that Ubs1p may represent a link between nucleocytoplasmic transport and ubiquitin ligase activity. Ubiquitin-dependent proteolysis of specific target proteins is required for several important steps during the cell cycle. Degradation of such proteins is strictly cell cycle-regulated and triggered by two large ubiquitin ligases, termed anaphase-promoting complex (APC) and Skp1/Cullin/F-box complex (SCF). Here we show that yeast Ran-binding protein 1 (Yrb1p), a predominantly cytoplasmic protein implicated in nucleocytoplasmic transport, is required for cell cycle regulated protein degradation. Depletion of Yrb1p results in the accumulation of unbudded G1cells and of cells arrested in mitosis implying a function of Yrb1p in the G1/S transition and in the progression through mitosis. Temperature-sensitive yrb1-51 mutants are defective in APC-mediated degradation of the anaphase inhibitor protein Pds1p and in degradation of the cyclin-dependent kinase inhibitor Sic1p, a target of SCF. Thus, Yrb1p is crucial for efficient APC- and SCF-mediated proteolysis of important cell cycle regulatory proteins. We have identified the UBS1 gene as a multicopy suppressor of yrb1-51 mutants. Ubs1p is a nuclear protein, and its deletion is synthetic lethal with a yrb1-51 mutation. Interestingly, UBS1 was previously identified as a multicopy suppressor of cdc34-2 mutants, which are defective in SCF activity. We suggest that Ubs1p may represent a link between nucleocytoplasmic transport and ubiquitin ligase activity. anaphase-promoting complex cyclin-dependent kinase Ran-binding protein Skp1/Cullin/F-box hemagglutinin green fluorescent protein There are three major transitions in the cell cycle of the budding yeast Saccharomyces cerevisiae: the G1/S transition when cells commit to replicate their genome, the metaphase to anaphase transition, when sister chromatids are separated, and the exit from mitosis, when the mitotic spindle is depolymerized and cytokinesis occurs. For efficient proliferation, cells must ensure the correct order of these events. Therefore, execution of these processes is tightly controlled.One important cell cycle regulator is the cyclin-dependent kinase Cdk1p, also called Cdc28p (1Morgan D.O. Annu. Rev. Cell Dev. Biol. 1997; 13: 261-291Crossref PubMed Scopus (1782) Google Scholar). Cdk1p is active only in association with a member of either the B-type cyclins Clb1-6p or the G1 cyclins Cln1-3p. Another important mechanism of cell cycle control is regulated protein degradation (2Hershko A. Curr. Opin. Cell Biol. 1997; 9: 788-799Crossref PubMed Scopus (318) Google Scholar, 3Jorgensen P. Tyers M. Curr. Opin. Microbiol. 1999; 2: 610-617Crossref PubMed Scopus (6) Google Scholar). Such proteins are targeted for proteolytic destruction by the formation of covalently linked chains of ubiquitin molecules. The final step of this fusion process, the ligation of activated ubiquitin to the substrate, is catalyzed by ubiquitin ligases. Two of these ubiquitin-protein isopeptide ligase enzymes are essential for cell cycle progression: the anaphase-promoting complex (APC),1 also called cyclosome, and the Skp1/Cullin/F-box (SCF) complex.Components of the SCF complex are Skp1p, the cullin protein Cdc53p, the ring finger protein Hrt1p, the ubiquitin-conjugating enzyme Cdc34p, and one of several F-box proteins such as Cdc4p (4Deshaies R.J. Annu. Rev. Cell Dev. Biol. 1999; 15: 435-467Crossref PubMed Scopus (1078) Google Scholar, 5Willems A.R. Goh T. Taylor L. Chernushevich I. Shevchenko A. Tyers M. Philos. Trans. R. Soc. Lond B. Biol. Sci. 1999; 354: 1533-1550Crossref PubMed Scopus (107) Google Scholar). SCF is constantly active throughout the cell cycle, but ubiquitination of specific SCF substrates is regulated by substrate phosphorylation. An essential role of SCF is the destruction of Sic1p, which is an inhibitor specific for Cdk1p associated with B-type cyclins (6Schwob E. Bohm T. Mendenhall M.D. Nasmyth K. Cell. 1994; 79: 233-244Abstract Full Text PDF PubMed Scopus (769) Google Scholar). At the G1/S transition, G1 cyclins Cln1p and Cln2p accumulate and activate Cdk1p to phosphorylate Sic1p (6Schwob E. Bohm T. Mendenhall M.D. Nasmyth K. Cell. 1994; 79: 233-244Abstract Full Text PDF PubMed Scopus (769) Google Scholar). Phosphorylated Sic1p is then rapidly degraded by the SCF complex (5Willems A.R. Goh T. Taylor L. Chernushevich I. Shevchenko A. Tyers M. Philos. Trans. R. Soc. Lond B. Biol. Sci. 1999; 354: 1533-1550Crossref PubMed Scopus (107) Google Scholar, 7Feldman R.M. Correll C.C. Kaplan K.B. Deshaies R.J. Cell. 1997; 91: 221-230Abstract Full Text Full Text PDF PubMed Scopus (712) Google Scholar). Thereby, Cdk1p associated with S phase cyclins Clb5p and Clb6p becomes active and triggers DNA replication.APC is a large protein complex that consists of at least 12 subunits inS. cerevisiae and is highly conserved in eukaroytes (8Morgan D.O. Nat. Cell Biol. 1999; 1: E47-E53Crossref PubMed Scopus (303) Google Scholar, 9Zachariae W. Nasmyth K. Genes Dev. 1999; 13: 2039-2058Crossref PubMed Scopus (570) Google Scholar). At the metaphase to anaphase transition, APC triggers sister chromatid separation by targeting the anaphase inhibitor Pds1p for destruction (10Cohen-Fix O. Peters J.M. Kirschner M.W. Koshland D. Genes Dev. 1996; 10: 3081-3093Crossref PubMed Scopus (675) Google Scholar). APC is also required for the mitotic exit. It triggers degradation of B-type cyclins leading to the inactivation of cyclin-dependent kinases (9Zachariae W. Nasmyth K. Genes Dev. 1999; 13: 2039-2058Crossref PubMed Scopus (570) Google Scholar, 11Zachariae W. Curr. Opin. Cell Biol. 1999; 11: 708-716Crossref PubMed Scopus (41) Google Scholar).Several yeast strains that are mutated in essential components of the nucleocytoplasmic transport machinery do not stop cell cycle progression randomly but show distinct cell cycle arrest phenotypes, predominantly in the G2/M phase. Such strains arecse1 (12Xiao Z. McGrew J.T. Schroeder A.J. Fitzgerald-Hayes M. Mol. Cell. Biol. 1993; 13: 4691-4702Crossref PubMed Scopus (112) Google Scholar), srp1 (13Loeb J.D. Schlenstedt G. Pellman D. Kornitzer D. Silver P.A. Fink G.R. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7647-7651Crossref PubMed Scopus (140) Google Scholar), yrb1 (14Ouspenski II Exp. Cell Res. 1998; 244: 171-183Crossref PubMed Scopus (23) Google Scholar), andsac3 (15Jones A.L. Quimby B.B. Hood J.K. Ferrigno P. Keshava P.H. Silver P.A. Corbett A.H. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 3224-3229Crossref PubMed Scopus (36) Google Scholar) mutants. These observations indicate an important role of nucleocytoplasmic transport for cell cycle progression. One of these mutants, srp1-31, was demonstrated to be defective in degradation of the mitotic cyclin Clb2p (13Loeb J.D. Schlenstedt G. Pellman D. Kornitzer D. Silver P.A. Fink G.R. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7647-7651Crossref PubMed Scopus (140) Google Scholar).A crucial component for nuclear transport in all eukaryotes is the small Ras-like GTPase Ran, which exists in a GTP- and a GDP-bound form (16Goldfarb D.S. Science. 1997; 276: 1814-1816Crossref PubMed Scopus (24) Google Scholar, 17Gorlich D. Kutay U. Annu. Rev. Cell Dev. Biol. 1999; 15: 607-660Crossref PubMed Scopus (1660) Google Scholar, 18Moore M.S. J. Biol. Chem. 1998; 273: 22857-22860Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). Ran is present both in the nucleus and in the cytoplasm, but the two Ran pools differ with respect to their GTP/GDP binding state; because of a cytosolic Ran GTPase activating protein (Ran-GAP), cytosolic Ran is predominantly in its GDP-bound form. In the nucleus, Ran is kept in its GTP-bound form by the action of a nuclear Ran guanine-nucleotide exchange factor. Apparently, this asymmetric distribution of the two forms of Ran is the driving force for nucleocytoplasmic transport.Most of the nuclear protein transport is mediated by a large superfamily of transport receptors, which are classified either as importins or as exportins, depending on the transport direction (19Pemberton L.F. Blobel G. Rosenblum J.S. Curr. Opin. Cell Biol. 1998; 10: 392-399Crossref PubMed Scopus (211) Google Scholar, 20Adam S.A. Curr. Opin. Cell Biol. 1999; 11: 402-406Crossref PubMed Scopus (76) Google Scholar). Importins and exportins differ with respect to the affinity for their substrates in the presence of RanGTP. Importins bind their substrate in the cytoplasm, where Ran-GTP is largely absent, and facilitate transport through the nuclear pore complex. In the nucleus, RanGTP binds to importin and thereby triggers the release of the substrate from the importin (21Rexach M. Blobel G. Cell. 1995; 83: 683-692Abstract Full Text PDF PubMed Scopus (662) Google Scholar, 22Gorlich D. Pante N. Kutay U. Aebi U. Bischoff F.R. EMBO J. 1996; 15: 5584-5594Crossref PubMed Scopus (527) Google Scholar), which is then transported back into the cytoplasm.Exportins bind their substrates cooperatively with RanGTP to form a trimeric complex (23Fornerod M. Ohno M. Yoshida M. Mattaj I.W. Cell. 1997; 90: 1051-1060Abstract Full Text Full Text PDF PubMed Scopus (1731) Google Scholar), which passages through the nuclear pore complex. Cytoplasmic dissociation of both RanGTP/importin and of RanGTP/exportin/cargo complexes requires the cytosolic Ran-binding protein 1 (RanBP1) (24Coutavas E. Ren M. Oppenheim J.D. D'Eustachio P. Rush M.G. Nature. 1993; 366: 585-587Crossref PubMed Scopus (226) Google Scholar). Binding of RanBP1 to RanGTP appears to trigger the transient formation of a RanGTP/RanBP1 dimer. In this dimer, RanGTP is accessible to RanGAP, which mediates GTP hydrolysis and renders complex disassembly irreversible (25Bischoff F.R. Gorlich D. FEBS Lett. 1997; 419: 249-254Crossref PubMed Scopus (202) Google Scholar, 26Floer M. Blobel G. Rexach M. J. Biol. Chem. 1997; 272: 19538-19546Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). Thus, RanBP1 appears to be a crucial factor for the recycling of transport factors and, as a consequence, for nuclear protein transport mediated by some of these receptors.The yeast homologue of the RanBP1 is encoded by the essentialYRB1 (yeast RanBP1) gene (27Butler G. Wolfe K.H. Biochim. Biophys. Acta. 1994; 1219: 711-712Crossref PubMed Scopus (13) Google Scholar, 28Ouspenski II Mueller U.W. Matynia A. Sazer S. Elledge S.J. Brinkley B.R. J. Biol. Chem. 1995; 270: 1975-1978Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 29Schlenstedt G. Saavedra C. Loeb J.D. Cole C.N. Silver P.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 225-229Crossref PubMed Scopus (168) Google Scholar). Temperature-sensitive mutants of YRB1 show defects in nuclear import and mRNA export (30Schlenstedt G. Wong D.H. Koepp D.M. Silver P.A. EMBO J. 1995; 14: 5367-5378Crossref PubMed Scopus (136) Google Scholar). 2M. Künzler, J. Trueheart, C. Sette, E. Hurt, and J. Thorner, submitted for publication. 2M. Künzler, J. Trueheart, C. Sette, E. Hurt, and J. Thorner, submitted for publication. Like other mutants implicated in nucleocytoplasmic transport, temperature-sensitiveyrb1 mutants were shown to be impaired in cell cycle progression (14Ouspenski II Exp. Cell Res. 1998; 244: 171-183Crossref PubMed Scopus (23) Google Scholar).In this study, we show that cells depleted of Yrb1p arrest either in G1 or in mitosis. These cell cycle defects prompted us to analyze whether Yrb1p is required for ubiquitin-mediated protein degradation during the cell cycle. We demonstrate thatyrb1-51 cells are impaired in proteolysis of crucial cell cycle regulatory proteins. The anaphase inhibitor Pds1p, a target of the APC and the CDK inhibitor Sic1p, whose degradation is normally triggered by the SCF, are both stabilized in these mutants. In a screen for high copy suppressors of yrb1-51, we have identifiedUBS1, which was previously identified as a putative positive regulator of Cdc34p, an ubiquitin-conjugating enzyme associated with SCF. Our data imply that Ran-binding protein Yrb1 is important for cell cycle-regulated proteolysis mediated by both the APC and SCF ubiquitin ligases and that Ubs1p may influence both the Ran pathway and ubiquitin ligases.DISCUSSIONIn this paper, we have analyzed the role of the Ran-binding protein 1 (Yrb1) in cell cycle progression in budding yeast. Yrb1p is a predominantly cytoplasmic protein implicated in nuclear import and export. A crucial role of Yrb1p in nucleocytoplasmic transport is thought to be the release of nuclear transport receptors from RanGTP in the cytoplasm. Thereby, Yrb1p is needed for the terminal step of nuclear export and for the recycling of import receptors (46Kehlenbach R.H. Dickmanns A. Kehlenbach A. Guan T. Gerace L. J. Cell Biol. 1999; 145: 645-657Crossref PubMed Scopus (175) Google Scholar).A Role for Yrb1p in Cell Cycle-regulated ProteolysisWe found that depletion of Yrb1p results in a cell cycle arrest either in G1 phase or in mitosis, and temperature-sensitiveyrb1-51 mutants fail to release from G1 or M phase arrests at their restrictive temperature. These data confirm and extend previous findings showing that mutants in Yrb1p display cell cycle arrest phenotypes (14Ouspenski II Exp. Cell Res. 1998; 244: 171-183Crossref PubMed Scopus (23) Google Scholar). Because ubiquitin-dependent proteolysis of specific target proteins is essential for cell cycle progression, we have particularly examined the role of Yrb1p in degradation of key regulatory proteins. We have shown here thatyrb1-51 mutants fail to degrade the anaphase inhibitor protein Pds1p, a substrate of the APC. Furthermore, mutant cells are sensitive against high levels of the mitotic cyclin Clb2p and thereby resemble mutants in the APC. We found that yrb1-51 mutants are also impaired in degradation of an inhibitor of cyclin-dependent kinases, Sic1p, a target of the SCF complex (Fig. 5), and another substrate of SCF, the transcription factor Gcn4p, is also stabilized in these mutants. 3R. Pries, personal communication. We conclude from these results that Yrb1p plays an important role in cell cycle-regulated proteolysis mediated by both the APC and SCF ubiquitin ligases.It was previously demonstrated that mutants in SRP1, encoding the yeast homologue of importin α, were unable to properly degrade Clb2p, suggesting that the nuclear import pathway is required for cyclin proteolysis (13Loeb J.D. Schlenstedt G. Pellman D. Kornitzer D. Silver P.A. Fink G.R. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7647-7651Crossref PubMed Scopus (140) Google Scholar). In contrast to yrb1-51,srp1-31 arrest predominantly in G2/M phase upon shift to their restrictive temperature, which may indicate that this importin is particularly important for proteolysis during mitosis. Our data imply that disruption of the Ran cycle stabilizes not only APC substrates but also SCF targets. Furthermore, cells lacking functional Yrb1p are impaired in the G1/S transition and in progression through mitosis.What could be the role of cytoplasmic Yrb1p in ubiquitin-dependent protein degradation? The findings thatsrp1 and yrb1 mutants are both impaired in this process implies that the obvious reason for this phenotype is their defect in nucleocytoplasmic transport. Impaired nuclear import or export may cause defects in ubiquitin ligase activity, for example by mislocalization of crucial components or regulators of the ubiquitination machinery. Alternatively, target proteins of ubiquitin ligases may be stabilized because they are not transported to locations where the ubiquitination machinery is active. At least in the case of the APC, which triggers the separation of sister chromatids, it is obvious that the important function of this ubiquitin ligase resides in the nucleus (9Zachariae W. Nasmyth K. Genes Dev. 1999; 13: 2039-2058Crossref PubMed Scopus (570) Google Scholar). However, it is yet unknown whether the activity of ubiquitin ligases is restricted to a specific cellular compartment.Another reason for the defect in proteolysis may be an impaired function of the proteasome. Indeed, recent findings showed that biogenesis of the 20 S proteasome depends on a functional nuclear protein import pathway. 4C. Enenkel, personal communication. As a consequence, cell cycle regulatory proteins targeted for destruction by ubiquitin ligases may get abnormally stabilized in yrb1-51mutants, because the proteasome is not properly active.It is also tempting to speculate that Yrb1p may have other important functions than in Ran-mediated transport. Independently of their role in nuclear transport, Ran and RanBP1 were found to be involved in the formation of the mitotic spindle in mammalian cells. RanGTPase apparently regulates the assembly of the mitotic spindle in a transport-independent manner (47Carazo-Salas R.E. Guarguaglini G. Gruss O.J. Segref A. Karsenti E. Mattaj I.W. Nature. 1999; 400: 178-181Crossref PubMed Scopus (398) Google Scholar, 48Kalab P. Pu R.T. Dasso M. Curr. Biol. 1999; 9: 481-484Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar, 49Azuma Y. Dasso M. Curr. Opin. Cell Biol. 2000; 12: 302-307Crossref PubMed Scopus (65) Google Scholar). It was also observed that RanBP1 levels oscillate during the cell cycle in mammalian cells and increased levels of RanBP1 disrupted various cell cycle events, such as the assembly of the mitotic spindle (41Battistoni A. Guarguaglini G. Degrassi F. Pittoggi C. Palena A. Di Matteo G. Pisano C. Cundari E. Lavia P. J. Cell Sci. 1997; 110: 2345-2357PubMed Google Scholar).It is unknown whether yeast Yrb1p has additional functions besides nucleocytoplasmic transport. Overexpression of YRB1and of GSP1 (the yeast RanGTPase) leads to an increased sensitivity toward the microtuble depolymerizing drug benomyl and to increased chromosome nondisjunction (28Ouspenski II Mueller U.W. Matynia A. Sazer S. Elledge S.J. Brinkley B.R. J. Biol. Chem. 1995; 270: 1975-1978Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). We found that cells arrested in mitosis because of the absence of Yrb1p displayed an abnormal mitotic spindle (Fig. 1 C). Thus, abnormal levels of Yrb1p, either increased or decreased, affect mitotic events, and these observed phenotypes might indicate that RanBP1 is important for spindle function also in lower eukaryotes.Although Yrb1p is localized predominantly in the cytoplasm and nuclear envelope breakdown during mitosis does not occur in this organism during mitosis, recent findings suggested that this Ran-binding protein may have a function in the nucleus. It was shown that Yrb1p shuttles between cytoplasm and nucleus (50Kunzler M. Gerstberger T. Stutz F. Bischoff F.R. Hurt E. Mol. Cell. Biol. 2000; 20: 4295-4308Crossref PubMed Scopus (47) Google Scholar, 51Plafker K. Macara I.G. Mol. Cell. Biol. 2000; 20: 3510-3521Crossref PubMed Scopus (56) Google Scholar). However, it remains to be shown whether its transient localization in the nucleus is important for Yrb1p function.Ubs1p, a Link of Yrb1p to Ubiquitin Ligase Activity?In a screen for multi-copy suppressors of the yrb1-51 mutation, we have identified the UBS1 gene that may represent a link between the Yrb1p and ubiquitin ligases. Interestingly, UBS1was initially identified as a multi-copy suppressor of cdc34mutants (45Prendergast J.A. Ptak C. Kornitzer D. Steussy C.N. Hodgins R. Goebl M. Ellison M.J. Mol. Cell. Biol. 1996; 16: 677-684Crossref PubMed Scopus (12) Google Scholar). Cdc34p is an ubiquitin-conjugating enzyme associated with SCF, and mutants in this essential gene are defective in SCF function causing a drastic stabilization of SCF target proteins such as Sic1p. Ubs1p has no homology to any other gene, and its function is unknown. Because high levels of Ubs1p suppressed the lethality ofcdc34 mutants, it was suggested that Ubs1p represents a putative positive regulator of Cdc34 (45Prendergast J.A. Ptak C. Kornitzer D. Steussy C.N. Hodgins R. Goebl M. Ellison M.J. Mol. Cell. Biol. 1996; 16: 677-684Crossref PubMed Scopus (12) Google Scholar). Interestingly, high copyUBS1 plasmids suppressed only some cdc34mutations but failed to suppress certain cdc34 mutations in a specific region on the surface of the proteins. Because this surface sequences resembled a region in Ubs1p itself, it was suggested that Ubs1p might directly bind to Cdc34p and thereby regulate its activity by interaction or by modification. However, such an interaction has not yet been demonstrated.A deletion of UBS1, which has no obvious effect on wild-type cells, is deleterious to both cdc34 (45Prendergast J.A. Ptak C. Kornitzer D. Steussy C.N. Hodgins R. Goebl M. Ellison M.J. Mol. Cell. Biol. 1996; 16: 677-684Crossref PubMed Scopus (12) Google Scholar) andyrb1-51 mutants at semipermissive temperatures. Thus, cells in which either Cdc34p or Yrb1p function is partially impaired are entirely dependent on Ubs1p. All these observations imply that Ubs1p promotes the function of both Yrb1p and Cdc34p.A GFP-Ubs1 fusion protein is localized to the nucleus (Fig. 7 E), and this nuclear localization is at least partially impaired in yrb1-51 mutants (data not shown). As suggested by Prendergast et al. (45Prendergast J.A. Ptak C. Kornitzer D. Steussy C.N. Hodgins R. Goebl M. Ellison M.J. Mol. Cell. Biol. 1996; 16: 677-684Crossref PubMed Scopus (12) Google Scholar), Ubs1p might be an activator of Cdc34p, and its nuclear import triggered by the RanGTP cycle may be important for proper SCF function in the nucleus. However, this simple explanation would not explain why high levels of Ubs1p also suppressyrb1-51 mutant cells. An alternative model, in which Ubs1p influences both nuclear transport and ubiquitin ligase activity, may be more likely. For example, Ubs1p may have a role in promoting nucleocytoplasmic transport and thereby accelerate nuclear localization of proteins, which induce SCF activity. The presence of high levels of this activatory protein then may cause suppression of a partially inactive Yrb1p. Accelerated transport by high levels of Ubs1p may then cause the nuclear accumulation of proteins that promote Cdc34/SCF activity leading to suppression of the cdc34 mutant. Such a model would explain why Ubs1p affects both yrb1 andcdc34 mutants.Nucleocytoplasmic Transport and the Regulation of Cell Cycle EventsAlthough it is possible that Yrb1p has essential roles other than nuclear import and export, cell cycle defect of mutants in several factors involved in nucleocytoplasmic transport, such assrp1, sac3, and cse1 mutants, suggests that functional transport is crucial for cell cycle progression. Mutants in the importin-α gene, SRP1, display defects in mitosis and cyclin proteolysis (13Loeb J.D. Schlenstedt G. Pellman D. Kornitzer D. Silver P.A. Fink G.R. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7647-7651Crossref PubMed Scopus (140) Google Scholar). Sac3p, a protein localized to the nuclear pore, is implicated in the progression through mitosis (15Jones A.L. Quimby B.B. Hood J.K. Ferrigno P. Keshava P.H. Silver P.A. Corbett A.H. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 3224-3229Crossref PubMed Scopus (36) Google Scholar). Cold-sensitive cse1-1 mutants, defective in the nuclear export receptor gene of Srp1p, arrest as large budded cells (12Xiao Z. McGrew J.T. Schroeder A.J. Fitzgerald-Hayes M. Mol. Cell. Biol. 1993; 13: 4691-4702Crossref PubMed Scopus (112) Google Scholar), and its mammalian homologue, CAS, was also implicated in mitosis (52Ogryzko V.V. Brinkmann E. Howard B.H. Pastan I. Brinkmann U. Biochemistry. 1997; 36: 9493-9500Crossref PubMed Scopus (29) Google Scholar).It is tempting to speculate that proteolysis of cell cycle regulatory proteins may be controlled by subcellular localization either of components of the destruction machinery or of the target proteins themselves. An example for regulated nuclear localization of a cell cycle regulatory protein is the transcription factor Swi5p. Swi5p is cytoplasmic until late anaphase, when it suddenly enters the nucleus and induces the transcription of late mitotic genes (53Moll T. Tebb G. Surana U. Robitsch H. Nasmyth K. Cell. 1991; 66: 743-758Abstract Full Text PDF PubMed Scopus (413) Google Scholar, 54Knapp D. Bhoite L. Stillman D.J. Nasmyth K. Mol. Cell Biol. 1996; 16: 5701-5707Crossref PubMed Scopus (109) Google Scholar). Phosphorylation of Swi5p by cyclin-dependent kinases prevents nuclear entry, and only the appearance of an antagonizing phosphatase, Cdc14p, allows nuclear import of Swi5p (55Visintin 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 (618) Google Scholar). Cdc14p is itself a well characterized example for regulated localization during the cell cycle. This phosphatase required for the mitotic exit is localized to the nucleolus for most of the cell cycle, and thereby it is kept inactive (56Shou W. Seol J.H. Shevchenko A. Baskerville C. Moazed D. Chen Z.W. Jang J. Charbonneau H. Deshaies R.J. Cell. 1999; 97: 233-244Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar, 57Visintin R. Hwang E.S. Amon A. Nature. 1999; 398: 818-823Crossref PubMed Scopus (486) Google Scholar). The release during anaphase allows Cdc14p to reach its targets, Swi5p, Sic1p, and Cdh1p, and the dephosphorylation of each of these proteins contributes to inactivation of cyclin-dependent kinases and the mitotic exit (11Zachariae W. Curr. Opin. Cell Biol. 1999; 11: 708-716Crossref PubMed Scopus (41) Google Scholar).In analogy to these proteins, the regulated localization of components of the destruction machinery may be a possible mechanism to ensure a precisely controlled degradation of target proteins, which is crucial for faithful cell cycle progression. To identify such regulatory proteins whose activity is controlled by nucleocytoplasmic transport is a task for future experiment. There are three major transitions in the cell cycle of the budding yeast Saccharomyces cerevisiae: the G1/S transition when cells commit to replicate their genome, the metaphase to anaphase transition, when sister chromatids are separated, and the exit from mitosis, when the mitotic spindle is depolymerized and cytokinesis occurs. For efficient proliferation, cells must ensure the correct order of these events. Therefore, execution of these processes is tightly controlled. One important cell cycle regulator is the cyclin-dependent kinase Cdk1p, also called Cdc28p (1Morgan D.O. Annu. Rev. Cell Dev. Biol. 1997; 13: 261-291Crossref PubMed Scopus (1782) Google Scholar). Cdk1p is active only in association with a member of either the B-type cyclins Clb1-6p or the G1 cyclins Cln1-3p. Another important mechanism of cell cycle control is regulated protein degradation (2Hershko A. Curr. Opin. Cell Biol. 1997; 9: 788-799Crossref PubMed Scopus (318) Google Scholar, 3Jorgensen P. Tyers M. Curr. Opin. Microbiol. 1999; 2: 610-617Crossref PubMed Scopus (6) Google Scholar). Such proteins are targeted for proteolytic destruction by the formation of covalently linked chains of ubiquitin molecules. The final step of this fusion process, the ligation of activated ubiquitin to the substrate, is catalyzed by ubiquitin ligases. Two of these ubiquitin-protein isopeptide ligase enzymes are essential for cell cycle progression: the anaphase-promoting complex (APC),1 also called cyclosome, and the Skp1/Cullin/F-box (SCF) complex. Components of the SCF complex are Skp1p, the cullin protein Cdc53p, the ring finger protein Hrt1p, the ubiquitin-conjugating enzyme Cdc34p, and one of several F-box proteins such as Cdc4p (4Deshaies R.J. Annu. Rev. Cell Dev. Biol. 1999; 15: 435-467Crossref PubMed Scopus (1078) Google Scholar, 5Willems A.R. Goh T. Taylor L. Chernushevich I. Shevchenko A. Tyers M. Philos. Trans. R. Soc. Lond B. Biol. Sci. 1999; 354: 1533-1550Crossref PubMed Scopus (107) Google Scholar). SCF is constantly active throughout the cell cycle, but ubiquitination of specific SCF substrates is regulated by substrate phosphorylation. An essential role of SCF is the destruction of Sic1p, which is an inhibitor specific for Cdk1p associated with B-type cyclins (6Schwob E. Bohm T. Mendenhall M.D. Nasmyth K. Cell. 1994; 79: 233-244Abstract Full Text PDF PubMed Scopus (769) Google Scholar). At the G1/S transition, G1 cyclins Cln1p and Cln2p accumulate and activate Cdk1p to phosphorylate Sic1p (6Schwob E. Bohm T. Mendenhall M.D. Nasmyth K. Cell. 1994; 79: 233-244Abstract Full Text PDF PubMed Scopus (769) Google Scholar). Phosphorylated Sic1p is then rapidly degraded by the SCF complex (5Willems A.R. Goh T. Taylor L. Chernushevich I. Shevchenko A. Tyer" @default.
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