Kaiser, P. et al. Cyclin-dependent kinase and Cks/Suc1 interact with the proteasome in yeast to control proteolysis of M-phase targets. Genes Dev. 13, 1190-1202

The Scripps Research Institute, MB7, La Jolla, California 92037, USA.
Genes & Development (Impact Factor: 10.8). 06/1999; 13(9):1190-202. DOI: 10.1101/gad.13.9.1190
Source: PubMed


Cell cycle-specific proteolysis is critical for proper execution of mitosis in all eukaryotes. Ubiquitination and subsequent proteolysis of the mitotic regulators Clb2 and Pds1 depend on the cyclosome/APC and the 26S proteasome. We report here that components of the cell cycle machinery in yeast, specifically the cell cycle regulatory cyclin-dependent kinase Cdc28 and a conserved associated protein Cks1/Suc1, interact genetically, physically, and functionally with components of the 26S proteasome. A mutation in Cdc28 (cdc28-1N) that interferes with Cks1 binding, or inactivation of Cks1 itself, confers stabilization of Clb2, the principal mitotic B-type cyclin in budding yeast. Surprisingly, Clb2-ubiquitination in vivo and in vitro is not affected by mutations in cks1, indicating that Cks1 is not essential for cyclosome/APC activity. However, mutant Cks1 proteins no longer physically interact with the proteasome, suggesting that Cks1 is required for some aspect of proteasome function during M-phase-specific proteolysis. We further provide evidence that Cks1 function is required for degradation of the anaphase inhibitor Pds1. Stabilization of Pds1 is partially responsible for the metaphase arrest phenotype of cks1 mutants because deletion of PDS1 partially relieves the metaphase block in these mutants.

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    • "The precise mechanism remains obscure but has been proposed to involve Cks1 recruitment of the proteasome to Cdc28 complexes [29]. Cks1 has been shown to physically interact with proteasome subunits [30]. Interestingly, while certain cks1 temperature-sensitive alleles confer G2/M delay [31], Clb cyclin-Cdc28 complexes do not require Cks1 for normal kinase activity [31,32]. "
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    ABSTRACT: Background The yeast cell cycle is largely controlled by the cyclin-dependent kinase (CDK) Cdc28. Recent evidence suggests that both CDK complex stability as well as function during mitosis is determined by precise regulation of Swe1, a CDK inhibitory kinase and cyclin binding partner. A model of mitotic progression has been provided by study of filamentous yeast. When facing nutrient-limited conditions, Ras2-mediated PKA and MAPK signaling cascades induce a switch from round to filamentous morphology resulting in delayed mitotic progression. Results To delineate how the dimorphic switch contributes to cell cycle regulation, temperature sensitive cdc28 mutants exhibiting constitutive filamentation were subjected to epistasis analyses with RAS2 signaling effectors. It was found that Swe1-mediated inhibitory tyrosine phosphorylation of Cdc28 during filamentous growth is in part mediated by Ras2 activation of PKA, but not Kss1-MAPK, signaling. This pathway is further influenced by Cks1, a conserved CDK-binding partner of elusive function with multiple proposed roles in CDK activation, transcriptional regulation and ubiquitin-mediated proteasome degradation. Conclusion The dynamic balance between Cks1- and Swe1-dependent regulation of Cdc28 and, thereby, the timing of mitosis during yeast dimorphism is regulated in part by Ras2/cAMP-mediated PKA signaling, a key pathway controlling filamentous growth.
    Cell Division 07/2009; 4. DOI:10.1186/1747-1028-4-12 · 3.53 Impact Factor
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    • "In a similar way, the CDK1–CycB–CKS complex phosphorylates the sub-unit CDC27 of the anaphase promoting complex, which is crucial for the ubiquitination of cyclin B and further exit from mitosis [10]. Once cyclin B has been ubiquitinated, interaction between the CKS and the proteasome is necessary for actual proteolysis of the cyclin [11] [12]. The human protein hCKS1 associates with SKP2, a subunit of the SCF-ubiquitin-ligase complex, and favors the ubiquitination of the CKI (cdk inhibitor) p27 Kip1 and thus the G1/S transition [13] [14]. "
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    ABSTRACT: The complex mechanism of cell division in trypanosomatids is not completely fully understood. CRKs (cdc2-related kinases), Cyclins and CKSs (cdc2-kinase subunit) are involved in the progression through the cell cycle. The CKS proteins were first described as components of the cell cycle machinery in yeast and their action has been implicated in the regulation of CDK function. In the present work we identified Tcp12CKS1 a member of the CKS family in the parasite Trypanosoma cruzi. TcCKS1 is expressed in the three forms of T. cruzi. By using anti-Tcp12CKS1 antiserum, protein kinase (PK) activities were immunoprecipitated. The PK activity level varies depending on the stage analyzed, being lower in trypomastigotes and thus suggesting that different stages have different CKS-CRK complexes. Moreover, these PK activities were inhibited by using Flavopiridol, a known CDKs inhibitor. Western blot analyses demonstrated that in the epimastigote stage, p12CKS1 stably interacts with TcCRK1 and TcCRK3. In addition, Tcp12CKS1 was able to rescue the p13SUC1 null mutant of S. pombe. The functional complementation between the CKS proteins of two evolutionary distant organisms supports the role of Tcp12CKS1 as a key regulator in T. cruzi cell cycle.
    Molecular and Biochemical Parasitology 07/2006; 147(2):154-62. DOI:10.1016/j.molbiopara.2006.02.006 · 1.79 Impact Factor
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    • "As a result, the mitosispromoting factor (MPF) becomes inactive because of the destruction of cyclin B, and the cell exits from the cycle before mitosis. Cks1 also plays a role here by helping unbiquitinated cyclin B to move toward the proteasome, where it is degraded, as demonstrated in budding yeast (Kaiser et al., 1999). Cks1 in Caenorhabditis elegans, one of the two Cks proteins in this organism, is also required for mitotic exit and for the completion of maternal meiotic divisions (Polinko and Strome, 2000). "
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    ABSTRACT: A full-length Cks1 homologue gene, AmphiCks1, was identified in amphioxus, Branchiostoma belcheri tsingtauense. Sequence characteristics, phylogeny and patterns of expression during embryonic and larval development were established. The protein predicted from AmphiCks1 showed high sequence identity with vertebrate and invertebrate homologues. Protein structural studies and phylogenetic analysis suggested that Cks homologues are evolutionarily conserved. The AmphiCks1 transcript was detected in most early developmental stages by northern blotting and whole-mount in situ hybridization, suggesting a role for the gene in cell division.
    Cell Biology International 08/2005; 29(7):593-7. DOI:10.1016/j.cellbi.2005.03.012 · 1.93 Impact Factor
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