CDC28/YBR160W Summary Help

Standard Name CDC28 1, 2
Systematic Name YBR160W
Alias CDK1 , HSL5 , SRM5
Feature Type ORF, Verified
Description Cyclin-dependent kinase (CDK) catalytic subunit; master regulator of mitotic and meiotic cell cycles; alternately associates with G1 (CLNs), S and G2/M (CLBs) phase cyclins, which provide substrate specificity; regulates cell cycle and basal transcription, chromosome duplication and segregation, lipid biosynthesis, membrane trafficking, polarized growth, and morphogenesis; abundance increases in DNA replication stress; transcript induction in osmostress involves antisense RNA (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and see Summary Paragraph)
Name Description Cell Division Cycle 16
Chromosomal Location
ChrII:560078 to 560974 | ORF Map | GBrowse
Gbrowse
Genetic position: 90 cM
Gene Ontology Annotations All CDC28 GO evidence and references
  View Computational GO annotations for CDC28
Molecular Function
Manually curated
High-throughput
Biological Process
Manually curated
High-throughput
Cellular Component
Manually curated
High-throughput
Regulators 3 genes
Resources
Classical genetics
conditional
null
reduction of function
Large-scale survey
conditional
null
overexpression
reduction of function
Resources
1023 total interaction(s) for 566 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 70
  • Affinity Capture-RNA: 1
  • Affinity Capture-Western: 53
  • Biochemical Activity: 396
  • Co-localization: 4
  • Co-purification: 8
  • PCA: 46
  • Protein-peptide: 2
  • Reconstituted Complex: 26
  • Two-hybrid: 36

Genetic Interactions
  • Dosage Growth Defect: 6
  • Dosage Lethality: 3
  • Dosage Rescue: 25
  • Negative Genetic: 41
  • Phenotypic Enhancement: 54
  • Phenotypic Suppression: 18
  • Positive Genetic: 5
  • Synthetic Growth Defect: 162
  • Synthetic Lethality: 37
  • Synthetic Rescue: 30

Resources
Expression Summary
histogram
Resources
Length (a.a.) 298
Molecular Weight (Da) 34,061
Isoelectric Point (pI) 8.5
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrII:560078 to 560974 | ORF Map | GBrowse
SGD ORF map
Genetic position: 90 cM
Last Update Coordinates: 2011-02-03 | Sequence: 1997-01-28
Subfeature details
Relative
Coordinates
Chromosomal
Coordinates
Most Recent Updates
Coordinates Sequence
CDS 1..897 560078..560974 2011-02-03 1997-01-28
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | E.C. | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000000364
SUMMARY PARAGRAPH for CDC28

Cdc28 is the catalytic subunit of the main cell cycle cyclin-dependent kinase (CDK) (17, 4). Homologs include CDK1 in animals and cdc2 in S. pombe. Waves of CDK activity drive events of the cell cycle through phosphorylation of key substrates (18, 19 and reviewed in 11). To accomplish these waves of activity, Cdc28p associates with different regulators throughout the cell cycle (20). The expression of several of these regulators is periodic which serves to limit their window of action to the proper time in the cell cycle (21, 22, 23, 24, 25, 26).

The first wave of CDK activity occurs when Cdc28p associates with G1 cyclins and Cks1p (27). The G1 cyclins are Cln1p, Cln2p, and Cln3p. Cln3p/Cdc28p activity is required for setting the size threshold at which cells pass through START (commitment to duplication and division) (28). Once committed Cln3p/Cdc28p inactivates a repressor of G1 transcription, Whi5p, which in turn leads to active SBF (Swi4p-Swi6p) and MBF (Mbp1p-Swi6p), transcription factors that promote transcription of CLN1, CLN2, and genes required for S-phase (29, 30, 31). Cln1p and Cln2p are important for initiating polarized growth at the site of bud emergence, promoting spindle pole body (SPB) duplication and inhibiting Sic1p and Cdh1p, two CDK inhibitors (32, 33). During G1, Sic1p binds and inhibits the growing pool of Cdc28p/B-type cyclin complexes. Towards the end of G1, Cdc28p/Cln1p and Cdc28p/Cln2p complexes phosphorylate Sic1p and target it for degradation. (34, 35). The absence of Sic1p allows a wave of CDK/B-cyclin activity that drives DNA replication and entry into mitosis (36).

B-type cyclins Clb1p, Clb2p, Clb3p, Clb4p, Clb5p, and Clb6p regulate Cdc28p during S, G2, and M phases. Cdc28p association with Clb5p and Clb6p drives DNA replication (37). Association with Clb3p, Clb4p, and Clb5p promotes maturation and separation of spindle pole bodies, and proper spindle segregation (38, 39, 40) while Cdc28p association with Clb2p (and to some extent Clb1p, Clb3p, and Clb4p) promotes entry into mitosis and triggers a switch in bud growth from polarized to isotropic (32, 41). The metaphase to anaphase transition occurs when securin (Pds1p), an inhibitor of DNA segregation is destroyed by the proteosome. Mitotic CDK activity is required to target Pds1p for degradation by directly phosphorylating Pds1p and activating the Anaphase Promoting Complex/Cyclosome (APC/C). (42, 43, 44).

Once DNA is segregated, exit from mitosis (spindle disassembly, cytokinesis and transition to the next G1) requires that mitotic CDK activity be turned off (45). This is accomplished by degradation of mitotic cyclins and inhibition of remaining mitotic activity by Sic1p. In the absence of mitotic CDK activity, G1 cyclins can once again accumulate (46, 43).

In addition to being regulated by binding partners, Cdc28p is regulated by post-translational modifications. Cak1p phosphorylation of Cdc28p on threonine 169 is essential for CDK activity and is thought to precede cyclin binding (47). Phosphorylation of Cdc28p on tyrosine 19 (Y19) by Swe1p kinase (wee1 in S. pombe) inhibits mitotic CDK activity and hence, entry into mitosis (48, 49, 50, 51, 52). This phosphorylation is removed by the phosphatase Mih1p (homolog of cdc25 in S. pombe) (53). Phosphorylation of Y19 is critical for enforcing the morphogenesis checkpoint. When cells experience an environmental perturbation that disrupts bud formation, the morphogenesis checkpoint delays entry into mitosis until a bud is formed. The checkpoint impinges on Swe1p and Mih1p to inactivate the mitotic CDK, insuring that mitosis does not occur in an unbudded cell (54, 55). Unlike in S. pombe and metazoans, Swe1p and/or Mih1p are not direct targets of the spindle checkpoints (56) or DNA checkpoints (57).

Developmental programs such as mating, meiosis and sporulation, and pseudohyphal growth require alterations in cell cycle control. For example, during mating, pheromone-dependent inhibition of Cln/Cdc28p complexes by Far1p arrests cells in G1 so cell-cell fusion can occur. When sporulation is induced, cells enter meiosis from G1, but CLN1 and CLN2 are repressed by a mechanism that makes meiosis and mitosis incompatible (58).

Last updated: 2006-08-09 Contact SGD

References cited on this page View Complete Literature Guide for CDC28
1) Nasmyth KA and Reed SI  (1980) Isolation of genes by complementation in yeast: molecular cloning of a cell-cycle gene. Proc Natl Acad Sci U S A 77(4):2119-23
2) Hartwell LH, et al.  (1973) Genetic Control of the Cell Division Cycle in Yeast: V. Genetic Analysis of cdc Mutants. Genetics 74(2):267-286
3) Reed SI  (1980) The selection of S. cerevisiae mutants defective in the start event of cell division. Genetics 95(3):561-77
4) Mendenhall MD and Hodge AE  (1998) Regulation of Cdc28 cyclin-dependent protein kinase activity during the cell cycle of the yeast Saccharomyces cerevisiae. Microbiol Mol Biol Rev 62(4):1191-243
5) Reed SI and Wittenberg C  (1990) Mitotic role for the Cdc28 protein kinase of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 87(15):5697-701
6) Wittenberg C, et al.  (1990) G1-specific cyclins of S. cerevisiae: cell cycle periodicity, regulation by mating pheromone, and association with the p34CDC28 protein kinase. Cell 62(2):225-37
7) Purnapatre K, et al.  (2002) The CLN3/SWI6/CLN2 pathway and SNF1 act sequentially to regulate meiotic initiation in Saccharomyces cerevisiae. Genes Cells 7(7):675-91
8) Benjamin KR, et al.  (2003) Control of landmark events in meiosis by the CDK Cdc28 and the meiosis-specific kinase Ime2. Genes Dev 17(12):1524-39
9) Hartwell LH  (1973) Three additional genes required for deoxyribonucleic acid synthesis in Saccharomyces cerevisiae. J Bacteriol 115(3):966-74
10) Kurat CF, et al.  (2009) Cdk1/Cdc28-dependent activation of the major triacylglycerol lipase Tgl4 in yeast links lipolysis to cell-cycle progression. Mol Cell 33(1):53-63
11) Enserink JM and Kolodner RD  (2010) An overview of Cdk1-controlled targets and processes. Cell Div 5():11
12) Chymkowitch P, et al.  (2012) Cdc28 kinase activity regulates the basal transcription machinery at a subset of genes. Proc Natl Acad Sci U S A 109(26):10450-5
13) McCusker D, et al.  (2012) Cdk1-dependent control of membrane-trafficking dynamics. Mol Biol Cell 23(17):3336-47
14) Tkach JM, et al.  (2012) Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress. Nat Cell Biol 14(9):966-76
15) Nadal-Ribelles M, et al.  (2014) Control of Cdc28 CDK1 by a Stress-Induced lncRNA. Mol Cell 53(4):549-61
16) Hartwell LH, et al.  (1970) Genetic control of the cell-division cycle in yeast. I. Detection of mutants. Proc Natl Acad Sci U S A 66(2):352-9
17) Lew DJ, et al.  (1997) "Cell cycle control in Saccharomyces cerevisiae." Pp. 607-695 in The Molecular and Cellular Biology of the Yeast Saccharomyces: Cell Cycle and Cell Biology, edited by Pringle JR, Broach JR and Jones EW. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press
18) Ubersax JA, et al.  (2003) Targets of the cyclin-dependent kinase Cdk1. Nature 425(6960):859-64
19) Loog M and Morgan DO  (2005) Cyclin specificity in the phosphorylation of cyclin-dependent kinase substrates. Nature 434(7029):104-8
20) Wittenberg C  (2005) Cell cycle: cyclin guides the way. Nature 434(7029):34-5
21) Dynlacht BD  (1997) Regulation of transcription by proteins that control the cell cycle. Nature 389(6647):149-52
22) Irniger S and Nasmyth K  (1997) The anaphase-promoting complex is required in G1 arrested yeast cells to inhibit B-type cyclin accumulation and to prevent uncontrolled entry into S-phase. J Cell Sci 110 ( Pt 13)():1523-31
23) Peters JM  (2002) The anaphase-promoting complex: proteolysis in mitosis and beyond. Mol Cell 9(5):931-43
24) Skowyra D, et al.  (1997) F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell 91(2):209-19
25) Skowyra D, et al.  (1999) Reconstitution of G1 cyclin ubiquitination with complexes containing SCFGrr1 and Rbx1. Science 284(5414):662-5
26) Kishi T and Yamao F  (1998) An essential function of Grr1 for the degradation of Cln2 is to act as a binding core that links Cln2 to Skp1. J Cell Sci 111 ( Pt 24)():3655-61
27) Reynard GJ, et al.  (2000) Cks1 is required for G(1) cyclin-cyclin-dependent kinase activity in budding yeast. Mol Cell Biol 20(16):5858-64
28) Cross FR  (1988) DAF1, a mutant gene affecting size control, pheromone arrest, and cell cycle kinetics of Saccharomyces cerevisiae. Mol Cell Biol 8(11):4675-84
29) de Bruin RA, et al.  (2004) Cln3 activates G1-specific transcription via phosphorylation of the SBF bound repressor Whi5. Cell 117(7):887-98
30) Costanzo M, et al.  (2004) CDK activity antagonizes Whi5, an inhibitor of G1/S transcription in yeast. Cell 117(7):899-913
31) Jorgensen P and Tyers M  (2004) How cells coordinate growth and division. Curr Biol 14(23):R1014-27
32) Lew DJ and Reed SI  (1995) Cell cycle control of morphogenesis in budding yeast. Curr Opin Genet Dev 5(1):17-23
33) Lew DJ and Reed SI  (1993) Morphogenesis in the yeast cell cycle: regulation by Cdc28 and cyclins. J Cell Biol 120(6):1305-20
34) Schneider BL, et al.  (1996) Linkage of replication to start by the Cdk inhibitor Sic1. Science 272(5261):560-2
35) Verma R, et al.  (1997) Phosphorylation of Sic1p by G1 Cdk required for its degradation and entry into S phase. Science 278(5337):455-60
36) Verma R, et al.  (2001) Selective degradation of ubiquitinated Sic1 by purified 26S proteasome yields active S phase cyclin-Cdk. Mol Cell 8(2):439-48
37) Schwob E and Nasmyth K  (1993) CLB5 and CLB6, a new pair of B cyclins involved in DNA replication in Saccharomyces cerevisiae. Genes Dev 7(7A):1160-75
38) Maekawa H and Schiebel E  (2004) Cdk1-Clb4 controls the interaction of astral microtubule plus ends with subdomains of the daughter cell cortex. Genes Dev 18(14):1709-24
39) Segal M, et al.  (2000) Coordinated spindle assembly and orientation requires Clb5p-dependent kinase in budding yeast. J Cell Biol 148(3):441-52
40) Haase SB, et al.  (2001) Multi-step control of spindle pole body duplication by cyclin-dependent kinase. Nat Cell Biol 3(1):38-42
41) Fitch I, et al.  (1992) Characterization of four B-type cyclin genes of the budding yeast Saccharomyces cerevisiae. Mol Biol Cell 3(7):805-18
42) Farr KA and Cohen-Fix O  (1999) The metaphase to anaphase transition: a case of productive destruction. Eur J Biochem 263(1):14-9
43) Harper JW, et al.  (2002) The anaphase-promoting complex: it's not just for mitosis any more. Genes Dev 16(17):2179-206
44) Nasmyth K  (2005) How do so few control so many? Cell 120(6):739-46
45) Surana U, et al.  (1993) Destruction of the CDC28/CLB mitotic kinase is not required for the metaphase to anaphase transition in budding yeast. EMBO J 12(5):1969-78
46) Irniger S  (2002) Cyclin destruction in mitosis: a crucial task of Cdc20. FEBS Lett 532(1-2):7-11
47) Ross KE, et al.  (2000) Activating phosphorylation of the Saccharomyces cerevisiae cyclin-dependent kinase, cdc28p, precedes cyclin binding. Mol Biol Cell 11(5):1597-609
48) Booher RN, et al.  (1993) Properties of Saccharomyces cerevisiae wee1 and its differential regulation of p34CDC28 in response to G1 and G2 cyclins. EMBO J 12(9):3417-26
49) Harvey SL, et al.  (2005) Cdk1-dependent regulation of the mitotic inhibitor Wee1. Cell 122(3):407-20
50) Sorger PK and Murray AW  (1992) S-phase feedback control in budding yeast independent of tyrosine phosphorylation of p34cdc28. Nature 355(6358):365-8
51) Hu F and Aparicio OM  (2005) Swe1 regulation and transcriptional control restrict the activity of mitotic cyclins toward replication proteins in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 102(25):8910-5
52) Amon A, et al.  (1992) Regulation of p34CDC28 tyrosine phosphorylation is not required for entry into mitosis in S. cerevisiae. Nature 355(6358):368-71
53) Russell P, et al.  (1989) Conservation of mitotic controls in fission and budding yeasts. Cell 57(2):295-303
54) Lew DJ  (2003) The morphogenesis checkpoint: how yeast cells watch their figures. Curr Opin Cell Biol 15(6):648-53
55) McNulty JJ and Lew DJ  (2005) Swe1p responds to cytoskeletal perturbation, not bud size, in S. cerevisiae. Curr Biol 15(24):2190-8
56) Lew DJ and Burke DJ  (2003) The spindle assembly and spindle position checkpoints. Annu Rev Genet 37():251-82
57) Chen Y and Sanchez Y  (2004) Chk1 in the DNA damage response: conserved roles from yeasts to mammals. DNA Repair (Amst) 3(8-9):1025-32
58) Wittenberg C and La Valle R  (2003) Cell-cycle-regulatory elements and the control of cell differentiation in the budding yeast. Bioessays 25(9):856-67