An Inhibitor of Yeast Cyclin-Dependent Protein Kinase Plays an Important Role in Ensuring the Genomic Integrity of Daughter Cells

Nugroho, Titania Tjandrawati; Mendenhall, Michael J.

doi:10.1128/mcb.14.5.3320-3328.1994

Cited by 18 publications

(7 citation statements)

References 47 publications

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“…CAS is the human homologue to a yeast chromosome segregation gene, and it has been shown that chromosome segregation genes can be cell cycle check points (Hartwell & Kastan, 1994;Nugroho & Mendenhall, 1994). Furthermore, involvement of CSE1 in B-type cyclin degradation has already been demonstrated (Irniger et al, 1995).…”

Section: T H Imentioning

confidence: 99%

Role ofCAS, a Human Homologue to the Yeast Chromosome Segregation GeneCSE1, in Toxin and Tumor Necrosis Factor Mediated Apoptosis

Brinkmann

Brinkmann²,

Gallo³

et al. 1996

Biochemistry

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We have previously isolated by expression/selection cloning plasmids containing human cDNAs that rendered MCF-7 breast cancer cells resistant to immunotoxins, Pseudomonas exotoxin (PE), and diphtheria toxin (DT) [Brinkmann et al. (1995) Mol. Med. 1, 206-216]. Here we describe that one of these resistant plasmids, which contains an antisense cDNA fragment homologous to the yeast chromosome segregation gene CSE1 [CAS; Brinkmann et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 10427-10431], reduces the intracellular content of the human CSE1 homologue CAS protein. CAS reduction confers resistance not only to the ADP-ribosylating toxins PE and DT, but also to tumor necrosis factor alpha and beta. The resistance was observed as reduced apoptosis. CAS antisense did not affect the cell death induced by staurosporine, cycloheximide, or etoposide. The observation that CAS antisense can interfere with apoptosis mediated by TNF and ADP-ribosylating toxins suggests that CAS may play a role in selected pathways of apoptosis.

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Section: T H Imentioning

confidence: 99%

Role ofCAS, a Human Homologue to the Yeast Chromosome Segregation GeneCSE1, in Toxin and Tumor Necrosis Factor Mediated Apoptosis

Brinkmann

Brinkmann²,

Gallo³

et al. 1996

Biochemistry

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“…In yeast, this complex is required for S‐phase entry and includes the products of the CDC34, CDC4, CDC53 and SKP1 genes (Bai et al ., 1996; Mathias et al ., 1996; Willems et al ., 1996; reviewed by Jackson, 1996; King et al ., 1996; Nasmyth, 1996). Genetic data imply that the essential substrate of this pathway for the G 1 –S transition is SIC1, an inhibitor of S‐phase cyclin–CDK complexes (Nugroho and Mendenhall, 1994; Schwob et al ., 1994). Other substrates include FAR1 (S.Henchoz, Y.Chi, B.Catarin, I.Herskowitz, R.Deshaies and M.Peter, submitted)_a CKI involved in pheromone‐induced arrest (Peter and Herskowitz, 1994)_and G 1 cyclins (CLN2 and 3) (Deshaies et al ., 1995; Yaglom et al ., 1995).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27Kip1

1997

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The p27Kip1 protein associates with G1‐specific cyclin–CDK complexes and inhibits their catalytic activity. p27Kip1 is regulated at various levels, including translation, degradation by the ubiquitin/proteasome pathway and non‐covalent sequestration. Here, we describe point mutants of p27 deficient in their interaction with either cyclins (p27c−), CDKs (p27k−) or both (p27ck−), and demonstrate that each contact is critical for kinase inhibition and induction of G1 arrest. Through its intact cyclin contact, p27k− associated with active cyclin E–CDK2 and, unlike wild type p27, p27c− or p27ck−, was efficiently phosphorylated by CDK2 on a conserved C‐terminal CDK target site (TPKK). Retrovirally expressed p27k− was rapidly degraded through the proteasome in Rat1 cells, but was stabilized by secondary mutation of the TPKK site to VPKK. In this experimental setting, exogenous wild‐type p27 formed inactive ternary complexes with cellular cyclin E–CDK2, was not degraded through the proteasome, and was not further stabilized by the VPKK mutation. p27ck−, which was not recruited to cyclin E–CDK2, also remained stable in vivo. Thus, selective degradation of p27k− depended upon association with active cyclin E–CDK2 and subsequent phosphorylation. Altogether, these data show that p27 must be phosphorylated by CDK2 on the TPKK site in order to be degraded by the proteasome. We propose that cellular p27 must also exist transiently in a cyclin‐bound non‐inhibitory conformation in vivo.

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“…CDK inhibitors are negative regulators of CDK–cyclin complexes. Some CDK inhibitors, like budding yeast Far1, seem to respond to extracellular signals such as the presence of mating pheromones (Chang and Herskowitz, 1990; Peter et al ., 1993; Peter and Herskowitz, 1994), but others, like budding yeast p40 SIC1 (Donovan et al ., 1994; Nugroho and Mendenhall, 1994; Schwob et al ., 1994; Schneider et al ., 1996) or fission yeast p25 rum1 (Moreno and Nurse, 1994), appear to be part of the intrinsic cell cycle machinery. While Far1 inhibits Cln‐type cyclins, p40 SIC1 and p25 rum1 are specific inhibitors of B‐type cyclins.…”

Section: Introductionmentioning

confidence: 99%

Regulation of the G1 phase of the cell cycle by periodic stabilization and degradation of the p25rum1 CDK inhibitor

1998

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In fission yeast, the cyclin-dependent kinase (CDK) inhibitor p25(rum1) is a key regulator of progression through the G1 phase of the cell cycle. We show here that p25(rum1) protein levels are sharply periodic. p25(rum1) begins to accumulate at anaphase, persists in G1 and is destroyed during S phase. p25(rum1 )is stabilized and polyubiquitinated in a mutant defective in the 26S proteasome, suggesting that its degradation normally occurs through the ubiquitin-dependent 26S proteasome pathway. Phosphorylation of p25(rum1 )by cdc2-cyclin complexes at residues T58 and T62 is important to target the protein for degradation. Mutation of one or both of these residues to alanine causes stabilization of p25(rum1) and induces a cell cycle delay in G1 and polyploidization due to occasional re-initiation of DNA replication before mitosis. The CDK-cyclin complex cdc2-cig1, which is insensitive to p25(rum1 )inhibition, seems to be the main kinase that phosphorylates p25(rum1). Phosphorylation of p25(rum1) in S phase and G2 serves as the trigger for p25(rum1) proteolysis. Thus, periodic accumulation and degradation of the CDK inhibitor p25(rum1 )in G1 plays a role in setting a threshold of cyclin levels important in determining the length of the pre-Start G1 phase and in ensuring the correct order of cell cycle events.

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An Inhibitor of Yeast Cyclin-Dependent Protein Kinase Plays an Important Role in Ensuring the Genomic Integrity of Daughter Cells

Cited by 18 publications

References 47 publications

Role ofCAS, a Human Homologue to the Yeast Chromosome Segregation GeneCSE1, in Toxin and Tumor Necrosis Factor Mediated Apoptosis

Role ofCAS, a Human Homologue to the Yeast Chromosome Segregation GeneCSE1, in Toxin and Tumor Necrosis Factor Mediated Apoptosis

Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27Kip1

Regulation of the G1 phase of the cell cycle by periodic stabilization and degradation of the p25rum1 CDK inhibitor

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