Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
S and G2 phase roles for Cdk2 revealed by inducible expression of a dominant-negative mutant in human cells.
Hu B, Mitra J, van den Heuvel S, Enders GH.
???displayArticle.abstract???
Cyclin-dependent kinase 2 (Cdk2) is essential for initiation of DNA synthesis in higher eukaryotes. Biochemical studies in Xenopus egg extracts and microinjection studies in human cells have suggested an additional function for Cdk2 in activation of Cdk1 and entry into mitosis. To further examine the role of Cdk2 in human cells, we generated stable clones with inducible expression of wild-type and dominant-negative forms of the enzyme (Cdk2-wt and Cdk2-dn, respectively). Both exogenous proteins associated efficiently with endogenous cyclins. Cdk2-wt had no apparent effect on the cell division cycle, whereas Cdk2-dn inhibited progression through several distinct stages. Cdk2-dn induction could arrest cells at the G1/S transition, as previously observed in transient expression studies. However, under normal culture conditions, Cdk2-dn induction primarily arrested cells with S and G2/M DNA contents. Several observations suggested that the latter cells were in G2 phase, prior to the onset of mitosis: these cells contained uncondensed chromosomes, low levels of cyclin B-associated kinase activity, and high levels of tyrosine-phosphorylated Cdk1. Furthermore, Cdk2-dn did not delay progression through mitosis upon release of cells from a nocodazole block. Although the G2 arrest imposed by Cdk2-dn was similar to that imposed by the DNA damage checkpoint, the former was distinguished by its resistance to caffeine. These findings provide evidence for essential functions of Cdk2 during S and G2 phases of the mammalian cell cycle.
Baber-Furnari,
Regulation of mitotic inhibitor Mik1 helps to enforce the DNA damage checkpoint.
2000, Pubmed
Baber-Furnari,
Regulation of mitotic inhibitor Mik1 helps to enforce the DNA damage checkpoint.
2000,
Pubmed Baum,
Cdc18 transcription and proteolysis couple S phase to passage through mitosis.
1998,
Pubmed Bunz,
Requirement for p53 and p21 to sustain G2 arrest after DNA damage.
1998,
Pubmed Chen,
Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists.
1999,
Pubmed Chen,
Association of Chk1 with 14-3-3 proteins is stimulated by DNA damage.
1999,
Pubmed Chew,
pRB phosphorylation mutants reveal role of pRB in regulating S phase completion by a mechanism independent of E2F.
1998,
Pubmed Clarke,
Dephosphorylation of cdc25-C by a type-2A protein phosphatase: specific regulation during the cell cycle in Xenopus egg extracts.
1993,
Pubmed
,
Xenbase Dai,
p16 INK4a can initiate an autonomous senescence program.
2000,
Pubmed De Bondt,
Crystal structure of cyclin-dependent kinase 2.
1993,
Pubmed De Souza,
Centrosomal and cytoplasmic Cdc2/cyclin B1 activation precedes nuclear mitotic events.
2000,
Pubmed Duncker,
Cyclin B-cdk1 kinase stimulates ORC- and Cdc6-independent steps of semiconservative plasmid replication in yeast nuclear extracts.
1999,
Pubmed
,
Xenbase Duronio,
E2F-induced S phase requires cyclin E.
1996,
Pubmed Duronio,
Developmental control of the G1 to S transition in Drosophila: cyclin Eis a limiting downstream target of E2F.
1995,
Pubmed Dynlacht,
Differential regulation of E2F transactivation by cyclin/cdk2 complexes.
1994,
Pubmed el-Deiry,
WAF1, a potential mediator of p53 tumor suppression.
1993,
Pubmed Elledge,
Cell cycle checkpoints: preventing an identity crisis.
1996,
Pubmed Elledge,
A new human p34 protein kinase, CDK2, identified by complementation of a cdc28 mutation in Saccharomyces cerevisiae, is a homolog of Xenopus Eg1.
1991,
Pubmed
,
Xenbase Enders,
p16 inhibition of transformed and primary squamous epithelial cells.
1996,
Pubmed Fang,
Evidence that the G1-S and G2-M transitions are controlled by different cdc2 proteins in higher eukaryotes.
1991,
Pubmed
,
Xenbase Furnari,
Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint kinase.
1997,
Pubmed Furuno,
Human cyclin A is required for mitosis until mid prophase.
1999,
Pubmed Gossen,
Tight control of gene expression in mammalian cells by tetracycline-responsive promoters.
1992,
Pubmed Guadagno,
Cdk2 kinase is required for entry into mitosis as a positive regulator of Cdc2-cyclin B kinase activity.
1996,
Pubmed
,
Xenbase Harkin,
Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1.
1999,
Pubmed Higashi,
Cyclin-dependent kinase-2 (Cdk2) forms an inactive complex with cyclin D1 since Cdk2 associated with cyclin D1 is not phosphorylated by Cdk7-cyclin-H.
1996,
Pubmed Hinchcliffe,
Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts.
1999,
Pubmed
,
Xenbase Hoffmann,
Phosphorylation and activation of human cdc25-C by cdc2--cyclin B and its involvement in the self-amplification of MPF at mitosis.
1993,
Pubmed
,
Xenbase Jeffrey,
Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex.
1995,
Pubmed Jiang,
Requirement of cyclin E-Cdk2 inhibition in p16(INK4a)-mediated growth suppression.
1998,
Pubmed Jin,
Role of inhibitory CDC2 phosphorylation in radiation-induced G2 arrest in human cells.
1996,
Pubmed Kinoshita,
Negative regulation of mitosis by the fission yeast protein phosphatase ppa2.
1993,
Pubmed Kitagawa,
The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2.
1996,
Pubmed Knighton,
Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase.
1991,
Pubmed Knighton,
Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase.
1991,
Pubmed Knoblich,
Synergistic action of Drosophila cyclins A and B during the G2-M transition.
1993,
Pubmed Knoblich,
Cyclin E controls S phase progression and its down-regulation during Drosophila embryogenesis is required for the arrest of cell proliferation.
1994,
Pubmed Knudsen,
Inhibition of DNA synthesis by RB: effects on G1/S transition and S-phase progression.
1998,
Pubmed Koff,
Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family.
1991,
Pubmed
,
Xenbase Krek,
Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of an S phase checkpoint.
1995,
Pubmed Krek,
Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase.
1994,
Pubmed Lacey,
Cyclin-dependent kinase control of centrosome duplication.
1999,
Pubmed
,
Xenbase Lukas,
Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex.
1999,
Pubmed Lundberg,
Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes.
1998,
Pubmed Matsuoka,
Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.
1998,
Pubmed McConnell,
Induced expression of p16(INK4a) inhibits both CDK4- and CDK2-associated kinase activity by reassortment of cyclin-CDK-inhibitor complexes.
1999,
Pubmed Meraldi,
Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A.
1999,
Pubmed Meyerson,
A family of human cdc2-related protein kinases.
1992,
Pubmed Michael,
Activation of the DNA replication checkpoint through RNA synthesis by primase.
2000,
Pubmed
,
Xenbase Mitra,
Induction of p21(WAF1/CIP1) and inhibition of Cdk2 mediated by the tumor suppressor p16(INK4a).
1999,
Pubmed Morgan,
Principles of CDK regulation.
1995,
Pubmed Morgenstern,
Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line.
1990,
Pubmed Nasmyth,
Viewpoint: putting the cell cycle in order.
1996,
Pubmed Ninomiya-Tsuji,
Cloning of a human cDNA encoding a CDC2-related kinase by complementation of a budding yeast cdc28 mutation.
1991,
Pubmed
,
Xenbase Ohtsubo,
Human cyclin E, a nuclear protein essential for the G1-to-S phase transition.
1995,
Pubmed Pagano,
Cyclin A is required at two points in the human cell cycle.
1992,
Pubmed Pagano,
Regulation of the cell cycle by the cdk2 protein kinase in cultured human fibroblasts.
1993,
Pubmed Petersen,
Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization.
1999,
Pubmed Poon,
Cyclin-dependent kinases are inactivated by a combination of p21 and Thr-14/Tyr-15 phosphorylation after UV-induced DNA damage.
1996,
Pubmed Poon,
The role of Cdc2 feedback loop control in the DNA damage checkpoint in mammalian cells.
1997,
Pubmed Qian,
Mitotic effects of a constitutively active mutant of the Xenopus polo-like kinase Plx1.
1999,
Pubmed
,
Xenbase Ruffner,
BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site.
1999,
Pubmed Sanchez,
Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25.
1997,
Pubmed Schlegel,
Caffeine-induced uncoupling of mitosis from the completion of DNA replication in mammalian cells.
1986,
Pubmed Scolnick,
Chfr defines a mitotic stress checkpoint that delays entry into metaphase.
2000,
Pubmed Sherr,
Cancer cell cycles.
1996,
Pubmed Shirahige,
Regulation of DNA-replication origins during cell-cycle progression.
1998,
Pubmed Spruck,
Deregulated cyclin E induces chromosome instability.
1999,
Pubmed Stoeber,
Cdc6 protein causes premature entry into S phase in a mammalian cell-free system.
1998,
Pubmed Stott,
The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2.
1998,
Pubmed Tsai,
The cdk2 kinase is required for the G1-to-S transition in mammalian cells.
1993,
Pubmed Tsai,
Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase.
1991,
Pubmed
,
Xenbase van den Heuvel,
Distinct roles for cyclin-dependent kinases in cell cycle control.
1993,
Pubmed Widrow,
Very late DNA replication in the human cell cycle.
1998,
Pubmed Winkler,
Requirement of the prolyl isomerase Pin1 for the replication checkpoint.
2000,
Pubmed
,
Xenbase Zarkowska,
Differential phosphorylation of the retinoblastoma protein by G1/S cyclin-dependent kinases.
1997,
Pubmed Zhang,
Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF.
2000,
Pubmed Zhang,
Active transcriptional repression by the Rb-E2F complex mediates G1 arrest triggered by p16INK4a, TGFbeta, and contact inhibition.
1999,
Pubmed Zhao,
Expression of NPAT, a novel substrate of cyclin E-CDK2, promotes S-phase entry.
1998,
Pubmed
