Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein phosphatase 1 and protein phosphatase 2A contain potential phosphorylation sites for cyclin-dependent kinases. In the present study we found that rabbit skeletal muscle protein phosphatase 1, as well as recombinant protein phosphatase 1 alpha and protein phosphatase 1 gamma 1, but not protein phosphatase 2A, was phosphorylated and inhibited by cdc2/cyclin A and cdc2/cyclin B. Phosphopeptide mapping and phospho amino acid analysis suggested that the phosphorylation site was located at a C-terminal threonine. Neither cdc2/cyclin A nor cdc2/cyclin B phosphorylated an active form of protein phosphatase 1 alpha in which Thr-320 had been mutated to alanine, indicating that the phosphorylation occurred at this threonine residue. Furthermore, protein phosphatase 1, but not protein phosphatase 2A, activity was found to change during the cell cycle of human MG-63 osteosarcoma cells. The observed oscillations in protein phosphatase 1 activity during the cell cycle may be due, at least in part, to phosphorylation of protein phosphatase 1 by cyclin-dependent kinases. Together, the results suggest a mechanism for direct regulation of protein phosphatase 1 activity.
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PMID:Phosphorylation and inactivation of protein phosphatase 1 by cyclin-dependent kinases. 802 97

The expression and intracellular localization of cyclin A and cdk2 have been analyzed in rat liver cells proliferatively activated in vivo by a partial hepatectomy. Western blot analysis revealed that cyclin A started to increase during G1 (at 6 h after hepatectomy) reaching maximal levels during S phase (at 18 h). Cdk2 began to increase during late G1 (at 12 h) peaking also at 18 h. At the latter time cyclin A was mainly localized in the microsomal fraction, although it was also present in cytosol, plasma membrane and nucleus. Active cyclin/cdks complexes containing cyclin A and cdk2 were obtained by precipitation with p13-Sepharose after solubilization of microsomes with triton X-100. The presence of active cyclin A/cdk2 complexes in microsomes was confirmed by immunoprecipitation experiments with anti-cdk2 antibodies. These results suggest a putative role of cyclin A/cdk2 during S phase which would be related with microsomal function.
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PMID:Microsomal localization of cyclin A and cdk2 in proliferating rat liver cells. 802 48

The 86 kDa immediate early IE2 protein of human cytomegalovirus (HCMV) can activate transcription of both viral and cellular genes and can repress transcription from its own promoter. Using two in vivo assays, we provide evidence of a functional interaction between IE2 and the retinoblastoma (RB) protein: IE2 alleviates RB-induced repression of a promoter bearing E2F binding sites and RB alleviates IE2-mediated repression of its own promoter. These functional effects are likely to be a result of a direct contact between IE2 and RB, which we can demonstrate both in vitro and in HCMV-infected cells. The interaction between IE2 and RB shows similar characteristics to the interaction between RB and E1A. First, binding to IE2 requires an intact RB pocket domain. Secondly, the binding is sensitive to the phosphorylation state of RB, because cyclin A-CDK-induced phosphorylation of RB diminishes IE2 binding. Thirdly, the IE2 domain required for RB binding is separate to the domains necessary for TBP and TFIIB binding. Our results demonstrate that large and small DNA viruses have a common interface with the host cell, namely the association with the RB tumour suppressor protein.
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PMID:Functional interaction between the HCMV IE2 transactivator and the retinoblastoma protein. 802 74

We cloned p27Kip1, a cyclin-dependent kinase inhibitor implicated in G1 phase arrest by TGF beta and cell-cell contact. p27Kip1 associates with cyclin E-Cdk2 complexes in vivo and in vitro, prevents their activation, and inhibits previously activated complexes, and p27Kip1 overexpression obstructs cell entry into S phase. p27Kip1 potently inhibits Rb phosphorylation by cyclin E-Cdk2, cyclin A-Cdk2, and cyclin D2-Cdk4. p27Kip1 is highly conserved and broadly expressed in human tissues, and its mRNA levels are similar in proliferating and quiescent cells. p27Kip1 has a region of sequence similarity to p21Cip1/WAF1, the Cdk inhibitor whose transcription is stimulated by p53. A p27Kip1 peptide corresponding to this region retains Cdk inhibitory activity. We suggest that cell contact, TGF beta, and p53 all restrain cell proliferation through related Cdk inhibitors.
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PMID:Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. 803 12

Using a yeast interaction screen to search for proteins that interact with cyclin D1-Cdk4, we identified a 27 kDa mouse protein related to the p21 cyclin-Cdk inhibitor. p27 interacts strongly with D-type cyclins and Cdk4 in vitro and more weakly with cyclin E and Cdk2. In mouse fibroblasts, p27 is associated predominantly with cyclin D1-Cdk4. Recombinant p27 is a potent inhibitor of cyclin D1-Cdk4 and cyclin A-Cdk2 protein kinase activity and a weaker inhibitor of cyclin B1-Cdc2. Overexpression of p27 in Saos-2 cells causes G1 arrest. p27 protein levels do not change as serum-stimulated quiescent mouse fibroblasts progress through the cell cycle. p27 is identical to p27Kip1, a cyclin-Cdk inhibitor present in TGF beta-treated cells. p27 has the hallmarks of a negative regulator of G1 progression and may mediate TGF beta-induced G1 arrest.
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PMID:p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. 803 13

While a large number of cyclins have been described in animals and yeasts, very limited information is available regarding cyclins in plants. We describe here the isolation of cDNA clones encoding four putative mitotic cyclins from maize. All four cyclins were able to induce maturation of Xenopus oocytes, demonstrating that they can act as mitotic cyclins in this system. Northern analysis showed that all four cyclins were expressed only in actively dividing tissues and organs, with a stronger correlation between expression and mitotic activity than is observed with cdc2. The deduced protein sequences suggest that the four maize cyclins belong to the cyclin A and B families identified from animal and yeast studies but that they cannot be described easily as either A-type or B-type cyclins. However, comparison with previously cloned plant cyclins shows that cyclins in higher plants form three distinct structural groups that have been conserved in both monocotyledonous and dicotyledonous species and that cyclins from all three groups are present within a single plant species.
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PMID:Cloning of four cyclins from maize indicates that higher plants have three structurally distinct groups of mitotic cyclins. 804 98

Butyrolactone I is a selective inhibitor of the cyclin-dependent kinase (cdk) family. It inhibits both cdk2 and cdc2 kinase, but scarcely affects C-kinase, A-kinase, casein kinases, MAP kinase or EGF receptor-tyrosine kinase (Kitagawa et al., 1993, Oncogene, 8, 2425-2432). We studied the effects of butyrolactone I on the cell cycle as well as on phosphorylation of retinoblastoma protein (pRB). Butyrolactone I inhibited phosphorylation of pRB catalyzed by cyclin A-cdk2 produced by baculovirus in vitro. Furthermore, it inhibited phosphorylation of pRB and cell cycle progression from G1 to S phase in WI38 cell cultures. WI38 cells arrested at the G0 phase by serum starvation progressed in the cell cycle after serum stimulation. pRB was phosphorylated after 10 h serum stimulation. Incorporation of [3H]thymidine into the cells began to increase after 16 h serum stimulation. These processes were inhibited by butyrolactone I. Flow cytometric analysis showed that exposure to butyrolactone I inhibited progression of the cell cycle from G1 to S phase. These data suggested that initiation of DNA synthesis was inhibited by butyrolactone I and that the cell cycle was arrested in the G1 phase. Butyrolactone I also inhibited H1 histone phosphorylation in human WI38 cells and their G2/M progression. tsFT210 cells, a temperature-sensitive cdc2 mutant cell line, were synchronized at G2/M at a nonpermissive temperature, butyrolactone I inhibited the cell cycle progression of these cells at G2/M at the permissive temperature. Thus butyrolactone I, a cyclin-dependent kinase family inhibitor, which prevented the phosphorylations of the cell cycle-regulating proteins pRB and H1 histone, inhibited the cell cycle at G1/S and G2/M, respectively. These results suggest that the phosphorylations of pRB and H1 histone may play crucial roles in G1/S and G2/M progression, respectively, although it is possible that phosphorylations of other proteins by cdks are involved in G1/S and G2/M progression.
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PMID:A cyclin-dependent kinase inhibitor, butyrolactone I, inhibits phosphorylation of RB protein and cell cycle progression. 805 18

We used targeted homologous recombination to disrupt one c-myc gene copy in a diploid fibroblast cell line and found that a twofold reduction in Myc expression resulted in lower exponential growth rates and a lengthening of the G0-to-S-phase transition (M. Shichiri, K. D. Hanson and J. M. Sedivy, Cell Growth Differ. 4:93-104, 1993). Myc is a transcription factor, and the number of target genes whose regulation could result in differential growth rates may be very large. We have approached this problem by examining effects of reduced c-myc expression in three broad areas: (i) secretion of growth factors, (ii) expression of growth factor receptors, and (iii) intracellular signal transduction between Myc and components of the intrinsic cell cycle clock. We have found no evidence that differential medium conditioning can account for the growth phenotypes. Likewise, the expression of receptors for platelet-derived growth factor, epidermal growth factor, basic fibroblast growth factor, and insulin-like growth factor I was the same in diploid and heterozygous cells (platelet-derived growth factor, epidermal growth factor, fibroblast growth factor, and insulin-like growth factor are the sole growth factors required by these cells for growth in serum-free medium). In contrast, expression of cyclin E, cyclin A, and Rb phosphorylation were delayed when quiescent c-myc heterozygous cells were stimulated to enter the cell cycle. Expression of cyclin D1, cyclin D3, and Cdk2 was not affected. The timing of cyclin E induction was the earliest observable effect of reduced Myc expression. Our data indicate that Myc contributes to regulation of proliferation by a cell-autonomous mechanism that involves the modulation of cyclin E expression and, consequently, progression through the restriction point of the cell cycle.
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PMID:Effects of c-myc expression on cell cycle progression. 806 9

We have shown previously that human cyclins A and B1 are localized differentially in the cell during interphase; cyclin A is nuclear and cyclin B1 is a cytoplasmic protein. To understand the basis of this difference we created deletion mutants and various chimeras between the two types of cyclin and expressed them in tissue culture cells by transient transfection. We find that the N-terminus of cyclin B1 contains a 42 amino acid region that is sufficient to retain the normally nuclear cyclin A in the cytoplasm. Conversely, deleting the cytoplasmic retention signal region from cyclin B1 causes the protein to become nuclear. Although the cytoplasmic retention signal region is outside the cyclin box, its sequence is well conserved in human cyclin B2, and is both necessary and sufficient to keep cyclin B2 in the cytoplasm. Thus we propose that the subcellular distribution of the B-type cyclins is determined primarily by a small region of the N-terminus which targets the cyclin--CDK complexes to particular structures in the cytoplasm.
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PMID:The differential localization of human cyclins A and B is due to a cytoplasmic retention signal in cyclin B. 807 Apr 5

RPA is a cellular, three-subunit, single-stranded (ss) DNA binding protein, which assists T-antigen in the assembly of the pre-priming complex in the SV40 replication system. By immunodepletion and complementation, we have identified RPA as an essential factor for cellular DNA replication in Xenopus extracts. RPA assembles post-mitotically on the decondensing chromosomes into numerous subnuclear pre-replication centres (preRCs) which serve, upon formation of the nuclear membrane, as RCs for the initiation of DNA synthesis. By a variety of experiments including the use of isolated components, we demonstrate that an inactive cdc2-cyclin B kinase complex is essential to allow post-mitotic assembly of the preRCs. In contrast, the active cdk2-cyclin A kinase does not impede or facilitate the assembly of preRCs. Digestion analysis using the single-strand-specific P1 nuclease as well as competition experiments with ssDNA, reveal that replication-associated unwinding of the DNA, assisted by RPA, requires the formation of the nuclear membrane. The p21 cdk-interacting protein Cip1 appears to inhibit DNA replication prior to the unwinding DNA step, but after assembly of preRC and nuclear reconstruction.
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PMID:Study of the cell cycle-dependent assembly of the DNA pre-replication centres in Xenopus egg extracts. 807 11


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