Disease relevance of CDC28

• A protein in yeast extracts can phosphorylate and activate Cdc7 protein made in Escherichia coli, and phosphorylation is thermolabile in cdc28 mutant extracts [1].
• CdtB toxicity is not circumvented in yeast genetically altered to lack DNA damage checkpoint control or that constitutively promote cell cycle progression via mutant Cdk1, because CdtB causes a permanent type of damage that results in loss of viability [2].
• Disjunction of conjoined twins: Cdk1, Cdh1 and separation of centrosomes [3].

Psychiatry related information on CDC28

• It has been suggested that hyperphosphorylation of the tau protein in neurofibrillary tangles may be relevant to the etiology of Alzheimer's disease and that at least one of the hyperphosphorylated sites lies within a consensus sequence for the p34cdc2/cdc28 family of kinases [4].

High impact information on CDC28

• We propose that this function of Cdc28 helps to coordinate the events of meiotic prophase with each other and with progression through prophase [5].
• Dephosphorylation of Cdk1 leads to further phosphorylation of Swe1 and release of Cdk1 [6].
• The Wee1 kinase phosphorylates and inhibits cyclin-dependent kinase 1 (Cdk1), thereby delaying entry into mitosis until appropriate conditions have been met [6].
• Clb4/Cdc28 kinase phosphorylates Kar9 and accumulates on the pole destined to the mother cell [7].
• Our results indicate that Cdk1-dependent spindle asymmetry ensures proper alignment of the mitotic spindle with the cell division axis [7].

Biological context of CDC28

• One simple model consistent with the roles of CDC28 and CDC37 in mitosis as well as in caryogamy is that these gene products are structural components of the nucleus that must be built into it during one cell cycle in order to permit successful caryogamy at the next G1 [8].
• Our results are consistent with CDC28 function being required in both G1 and mitosis [9].
• We conclude from our results that the KAR1, CDC28, and CDC37 gene products can diffuse between nuclei in a heterocaryon and that they probably perform their function for caryogamy prior to cell fusion [8].
• An internally deleted nonfunctional cln2 gene was used as a reporter gene to demonstrate that in the absence of mating pheromone, efficient expression of cln2 mRNA requires both an active CDC28 gene and at least one functional CLN gene. mRNA from a nonfunctional cln1 gene was regulated similarly [10].
• Rescue of this strain by mutant CDC28 was dependent upon the mutant cln2-KAEA, but additional mutagenesis and DNA shuffling yielded multiply mutant CDC28-BYC alleles (bypass of CLNs) that could support highly efficient cell cycle initiation in the complete absence of CLN genes [11].

Anatomical context of CDC28

• In this report, we show that a novel mutant allele of the CDC28 gene, encoding the budding yeast CDK, allowed cell cycle passage through mitosis and nuclear division in the presence of DNA damage and the microtubule toxin nocodazole at a restrictive temperature [12].
• The proportion of CDC28 gene product associated with the particulate fraction, and perhaps the insoluble matrix, appears to be substantially decreased during the preparation of spheroplasts [13].
• One deduced amino acid sequence shares 72% identity with rabbit skeletal muscle phosphorylase kinase gamma-subunit, while another is closely related to the yeast protein-serine kinases CDC2 in Schizosaccharomyces pombe and CDC28 in Saccharomyces cerevisiae [14].
• It has been suggested that cyclin-dependent kinase Cdc28, in complex with cyclin Clb4, associates only with the SPB in the mother cell and so prevents Kar9 binding to this SPB [15].
• Cdk1 regulates centrosome separation by restraining proteolysis of microtubule-associated proteins [16].

Associations of CDC28 with chemical compounds

• An increase of 300% to 400% in the expression of CDC28 (CDC28-lacZ) with a noticeable shortening in G1 to values lower than approximately 150 min, was detected in the transformed wild type CEN.SC13-9B in glucose-limited chemostat cultures [17].
• Moreover, tetracycline-dependent repression of YEF3, CDC28 and RAM2 expression impaired cell growth [18].
• The Swe1 protein kinase phosphorylates tyrosine residue 19 of Cdc28 and inhibits its activity [19].
• Far1-22p harbors a single amino acid change, from serine to proline at residue 87, which alters phosphorylation by Cdc28p-Cln2p in vitro [20].
• Glutamic acid can substitute for phosphothreonine in some proteins activated by phosphorylation, but this substitution (T169E) at the site of activation loop phosphorylation in the Saccharomyces cerevisiae cyclin-dependent kinase (Cdk) Cdc28p blocks biological function and protein kinase activity [21].

Physical interactions of CDC28

• Inactivation of the Cln-Cdc28p kinase complex by thermal inactivation of temperature-sensitive Cdc28p prevented repression of FUS1 signaling [22].
• Although Pho85 is not essential for viability, Pcl1,2-Pho85 kinase complexes become essential for Start in the absence of Cln1,2-Cdc28 kinases [23].
• In particular, the G2/M transition is initiated by the activity of a complex formed by a CDK of the Cdc2/Cdc28 family and B-type cyclins of the Cdc13/C1b family in the yeasts, Schizosaccharomyces pombe (Sp) and Saccharomyces cerevisiae (Sc) [24].
• We found that, when separately expressed, the N-terminal lobe of Cdc28 interacted strongly with the C-terminal moiety of Cdc37 in a two-hybrid system [25].
• We showed recently that a screen for mutant CDC28 with improved binding to a defective Cln2p G1 cyclin yielded a spectrum of mutations similar to those yielded by a screen for intragenic suppressors of the requirement for activation loop phosphorylation (T169E suppressors) [26].

Enzymatic interactions of CDC28

• We propose that Cdc28p is normally phosphorylated by Cak1p before it binds cyclin [27].
• Cln3 associates with Cdc28 to form an active kinase complex that phosphorylates Cln3 itself and a co-precipitated substrate of 45 kDa [28].
• Cdc14p mediates mitotic exit by dephosphorylating Cdk1p substrates and promoting Cdk1p inactivation [29].
• During vegetative growth, Ste5p is basally phosphorylated through a process regulated by the CDK Cdc28p [30].
• Two serines near the C-terminus of Cdc3 are phosphorylated in a Cdc28-dependent manner [31].

Regulatory relationships of CDC28

• Thus, CLN function and CDC28 activity jointly stimulate CLN1 and CLN2 mRNA levels, potentially forming a positive feedback loop for CLN1 and CLN2 expression [10].
• CAK1 promotes meiosis and spore formation in Saccharomyces cerevisiae in a CDC28-independent fashion [32].
• Cln2 and Cdc28 subunits coexpressed in baculovirus-infected insect cells fail to exhibit protein kinase activity towards multiple substrates in the absence of Cks1 [33].
• A Ser-230 to Ala mutation in the consensus sequence (SPIK) recognized by cdc2/CDC28-related kinase in PHO2 protein led to complete loss of its ability to activate the transcription of PHO5 gene [34].
• Phosphorylation by Cdc28 activates the Cdc20-dependent activity of the anaphase-promoting complex [35].

Other interactions of CDC28

• The CLN3-2 (DAF1-1) allele prevents both cell cycle arrest and the turnoff of CLN1 and CLN2 mRNAs in response to mating pheromone, but only in the presence of an active CDC28 gene [10].
• We show here that CLB2 proteolysis, which is important for transition from mitosis to G1, is not confined to a narrow window at the end of mitosis as previously thought but continues until reactivation of CDC28 by CLN cyclins toward the end of the subsequent G1 period [36].
• Entry into the mitotic cycle (START) requires a protein kinase encoded by the CDC28 gene and one of three redundant G1-specific cyclins encoded by CLN1, -2, and -3 [37].
• SGV1 encodes a CDC28/cdc2-related kinase required for a G alpha subunit-mediated adaptive response to pheromone in S. cerevisiae [38].
• The KSS1 gene encodes an apparent protein kinase homologous to the CDC28 (S. cerevisiae) and cdc2+ (S. pombe) gene products [39].
• A mutant form of a Cdc24-associated protein that fails to undergo Cdk1-dependent phosphorylation causes defects in bud growth [40].

Analytical, diagnostic and therapeutic context of CDC28

• Two hybrid assays showed that yeast CDC28 could interact with PHO2 [34].
• By using immunofluorescence methods, the CDC28 product was shown to be primarily cytoplasmic in distribution [13].
• A portion of the CDC28 product was found to be tightly associated with these detergent-insoluble cytoplasmic matrices by both immunofluorescence and immunoblotting procedures [13].
• Sequence analysis of temperature-sensitive mutations in the Saccharomyces cerevisiae gene CDC28 [41].
• Molecular cloning and analysis of CDC28 and cyclin homologues from the human fungal pathogen Candida albicans [42].

References