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)

Human cyclin E, originally identified on the basis of its ability to function as a G1 cyclin in budding yeast, associated with a cell cycle-regulated protein kinase in human cells. The cyclin E-associated kinase activity peaked during G1, before the appearance of cyclin A, and was diminished during exit from the cell cycle after differentiation or serum withdrawal. The major cyclin E-associated kinase in human cells was Cdk2 (cyclin-dependent kinase 2). The abundance of the cyclin E protein and the cyclin E-Cdk2 complex was maximal in G1 cells. These results provide further evidence that in all eukaryotes assembly of a cyclin-Cdk complex is an important step in the biochemical pathway that controls cell proliferation during G1.
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PMID:Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. 138 88

Kinases of the mammalian cdc2 family including cdk2 (cyclin-dependent kinase 2) are thought to be involved in both the G2/M transition and DNA replication. To investigate the role of cdc2 kinase and cdk2 in cell cycle progression, murine tsFT210 cells bearing a temperature-sensitive cdc2 mutation were used. These kinases were purified by column chromatography, using a peptide with the consensus phosphorylation site of cdc2 kinase as the substrate. In this mutant, cdc2 kinase activity was temperature sensitive and cdk2 activity was not. At the restrictive temperature, the mutant was only arrested in the G2 phase and not in the G1-S phase, suggesting that cdk2 did not compensate for cdc2 kinase at the G2/M transition but did function at the G1-S phase. This suggestion was supported by the finding that transfection of cdk2 cDNA did not improve the growth of the mutant cell line at the restrictive temperature, although transfection of cdc2 cDNA did.
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PMID:Cyclin-dependent kinase 2 (cdk2) in the murine Cdc2 kinase TS mutant. 147 6

Cyclins are regulatory subunits which associate with kinases to form complexes that control many of the important steps in cell-cycle progression. The best characterized of the cyclin-containing complexes is the association of cyclin B with the p34cdc2 kinase. The p34cdc2/cyclin B complex is required for the G2 to M transition (see refs 1-4 for review), but the physiological role of other cyclin complexes is unclear. Human cyclin A binds independently to two kinases, associating with either p34cdc2 or a related protein, p33 (refs 5-7). In adenovirus-transformed cells, the viral E1A oncoprotein seems to associate with p33/cyclin A but not with p34cdc2/cyclin A (B. Faha, M.M., L-H.T. and E.H., manuscript submitted). To isolate the gene for p33, we have cloned several novel human cdc2-related genes. The protein product of one of these genes, cdk2 (cyclin-dependent kinase 2), shares 65% sequence identity with p34cdc2 (ref. 8) and 89% identity with the Xenopus Eg-1 gene product. Immunochemical characterization and partial proteolytic mapping show that the cdk2 gene product is the cyclin A-associated p33. Immunoprecipitations of the p33cdk2 protein suggest that it can act as a protein kinase in vitro. As p33cdk2 is bound to cyclin A and is targeted by the viral E1A protein, we suggest that the p33cdk2/cyclin A complex has a unique role in cell-cycle regulation of vertebrate cells.
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PMID:Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase. 165 4

The p130 protein is a recently cloned member of the retinoblastoma protein family. We show here that transformation of NIH3T3-L1 fibroblasts (L1 cells) by the simian virus 40 large T antigen (LTAg) depends on the disruption of DNA binding complexes between transcription factor E2F and p130. LTAg binds to the pocket region of p130 in vivo and disrupts the E2F-p130 complexes. E2F-p130 complexes are present only in quiescent L1 cells and disappear at the G1/S phase boundary concomitantly to induction of DNA synthesis and expression of the E2F-regulated cdc2 gene. p130 is a substrate of cyclin-dependent kinase 2 (Cdk2) in vitro and associates with a Cdk in vivo which is activated upon serum stimulation in late G1. Overexpression of p130 inhibits cdc2 promoter activity and entry of quiescent L1 cells into S phase. The results demonstrate that p130 is negative regulator of cell cycle progression which is specifically targeted by LTAg during cell transformation.
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PMID:A complex between E2F and the pRb-related protein p130 is specifically targeted by the simian virus 40 large T antigen during cell transformation. 778 51

Transforming growth factor beta 1 (TGF-beta 1) is known to inhibit epithelial cell growth by inducing a G1 cell cycle arrest. We have studied the effect of TGF-beta 1 on protein binding to a transcription factor E2F consensus element in extracts from early passage human keratinocytes (HFKs) and a permanent human keratinocyte cell line (HaCaT). Treatment of these cells with TGF-beta 1 resulted in the formation of a DNA binding complex between the pRb-related protein p130 and E2F. Formation of the E2F-p130 complex correlated with inhibition of cell cycle progression in G1 and suppression of the E2F-regulated cdc2 gene. While p130 mRNA and protein levels were not influenced by TGF-beta 1, the activity of cyclin-dependent kinase 2 (Cdk2) towards p130 in vitro was inhibited. The results identify p130 as a downstream target of TGF-beta 1 and a possible mediator of the G1 cell cycle arrest.
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PMID:The pRb-related protein p130 is a possible effector of transforming growth factor beta 1 induced cell cycle arrest in keratinocytes. 778 52

CDK2 (cyclin-dependent kinase 2) is a serine/threonine kinase which is involved in regulating S-phase entry in higher eukaryotes. To investigate the transcriptional control of this gene, a 13-kb Xenopus laevis genomic clone containing the 5' flanking sequences was isolated. A 2.7-kb fragment containing the promoter region was sequenced and the transcription start point (tsp) was determined by primer extension. Several putative regulatory elements, such as the E2F-binding site, Y box and octamer-binding site, were localized in this region, but no TATA box was found. When fused to cat, a reporter gene encoding chloramphenicol acetyltransferase, the 5' flanking sequences were shown to function in oocytes and an enhancer activity was found in this region. During early embryogenesis, cdk2 promoter activity was tested and de novo transcription was detected at the mid-blastula transition.
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PMID:Cloning of the Xenopus laevis cdk2 promoter and functional analysis in oocytes and during early development. 782 9

Rat fibroblasts transformed by a temperature-sensitive mutant of murine p53 undergo a reversible growth arrest in G1 at 32.5 degrees C, the temperature at which p53 adopts a wild-type conformation. The arrested cells contain inactive cyclin-dependent kinase 2 (cdk2) despite the presence of high levels of cyclin E and cdk-activating kinase activity. This is due in part to p53-dependent expression of the p2l cdk inhibitor. Upon shift to 39 degrees C, wild-type p53 is lost and cdk2 activation and pRb phosphorylation occur concomitantly with loss of p2l. This p53-mediated growth arrest can be abrogated by overexpression of cdk4 and cdk6 but not cdk2 or cyclins, leading to continuous proliferation of transfected cells in the presence of wild-type p53 and p2l. Kinase-inactive counterparts of cdk4 and cdk6 also rescue these cells from growth arrest, implicating a noncatalytic role for cdk4 and cdk6 in this resistance to p53-mediated growth arrest. Aberrant expression of these cell cycle kinases may thus result in an oncogenic interference with inhibitors of cell cycle progression.
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PMID:Inhibition of p53-mediated growth arrest by overexpression of cyclin-dependent kinases. 875 45

The experiments described in this report were undertaken to define the parameters that regulate cyclin E/cyclin-dependent kinase 2 (Cdk2) kinase activity in mitotically quiescent, serum-starved fibroblastic cells and in cells that had been stimulated to enter the cell cycle and progress through G1 into S phase. We have analyzed the expression of cyclin E and Cdk2, the extent to which these two proteins form complexes, and the enzymatic activity of cyclin E/cdk2 kinase. Particular attention was focused upon subcellular localization and the effect of compartmentalization on the association between cyclin E and Cdk2. In addition, we have examined the interaction of cyclin E/Cdk2 complexes with two well-characterized inhibitors of Cdk2 kinase activity, Cip1 and Kip1. This represents the first report in which all of these parameters have been measured simultaneously in a single, normal diploid cell line. In G0 cells, there is abundant cyclin E and Cdk2, yet there is little or no detectable Cdk2-dependent histone H1 kinase activity. After serum stimulation, there is a rapid increase in the amount of cyclin E that is bound to Cdk2, although there is no significant change in the abundance of either the cyclin or the Cdk. Immunocytochemical data indicate that cyclin E, Cip1, and Kip1 are located within the nuclei of cell in G0, but very little Cdk2 is observed within the nuclei of serum-starved cells. Cdk2 rapidly enters the nucleus upon serum stimulation. The abundance of the cyclin E/Cdk2 complex increases to the extent that the binding capacity of Cip1 is exceeded about 8-12 h after serum stimulation. The abundance of Kip1 decreases at the same time that the Cip1 threshold is exceeded, so that cyclin E/Kip1-containing complexes decrease by 90% within 8-12 h. Cyclin E/Cdk2 kinase activity begins to increase rapidly thereafter, reaching a maximum level about 16 h after serum stimulation. We have been unable to detect histone H1 kinase activity in complexes that contain cyclin E bound to Kip1 or Cip1. We conclude that compartmentalization is the predominant barrier to activation of cyclin E-dependent kinases in quiescent cells. Cip1 and Kip1 serve to prevent premature activation of cyclin E/Cdk2 complexes that form during G0 or early G1.
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PMID:Cyclin E/Cdk2 activity is controlled by different mechanisms in the G0 and G1 phases of the cell cycle. 889 32

If exposure to xenoestrogens or electromagnetic fields (EMFs) such as 60 Hz contributes to the etiology of breast cancer, it is likely that they must stimulate the growth of breast cells, damage genetic material or enhance the effects of other mitogenic or mutagenic agents (co-promotion). Therefore, the ability of xenoestrogens or exposure to 60-Hz fields to stimulate the entry of growth-arrested human breast cancer cells into the cell cycle was determined using cyclin-dependent kinase 2 (Cdk2) activity, synthesis of cyclin D1 and cdc2 activity. Exposure of estrogen receptor-positive MCF-7 or T-47D cells to estrogen and xenoestrogens (DDT and Red No. 3) increased Cdk2 and cyclin B1-cdc2 activity and cyclin D1 synthesis. Exposure of breast cancer cells to 12 mG or 1 or 9 G electromagnetic fields at 60 Hz failed to stimulate Cdk2 or cyclin B1-cdc2 activity or cyclin D1 synthesis. Simultaneous co-exposure of cells to 60-Hz fields and chemical promoters did not enhance Cdk2 activation above the levels produced by the chemical promoter alone. Estrogen and xenoestrogens also stimulated binding of the estrogen receptor to the estrogen receptor element but the EMF did not. Phorbol 12-myristate 13-acetate (PMA) induced phosphorylation of p53 and pRb1O5 in MCF-7 cells, but EMF exposure had no effect. DNA-damaging chemotherapeutic agents and Red Dye No. 3 were found to increase p53 site-specific DNA binding in breast cancer cells, but EMF exposure did not. Differential display analysis failed to detect any effect of EMF exposure on gene expression in MCF-7 cells, whereas the effects of estradiol were detected. These studies suggest that estrogen and xenoestrogens stimulate growth-arrested breast cancer cells to enter the growth cycle, but EMF exposure does not. Site-specific p53-DNA binding was increased in MC F-7 cells treated with DNA-damaging agents, but not by EMF exposure. EMF exposure does not appear to act as a promoter or DNA-damaging agent for human breast cancer cells in vitro.
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PMID:Effects of 60-Hz fields, estradiol and xenoestrogens on human breast cancer cells. 892 16

We tested the ability of synthetic peptides derived from p21(WAF1), fused to the internalization peptide sequence derived from Antennapedia, to inhibit the growth of cancer cells in two human ovarian cancer cell lines expressing wild-type p53 or not. Two fused peptides corresponding to p21(WAF1) regions 17-33 and 63-77 inhibited cell growth in both cell lines while the same peptides without the internalization sequence were inactive. The fused peptides prevented growth at concentrations which inhibited cyclin-dependent kinase 2 and cdc2 activity, thus demonstrating that the peptides act by mimicking the action of p21(WAF1) on kinases. This study illustrates the potential pharmacological use of small peptides fused with the Antennapedia internalization sequence in proliferative disorders. The approach may be extended to other diseases in which cell penetration of a peptide may be of therapeutic benefit. More stable drug-like molecules with better pharmacological properties could be designed based on the results obtained with peptides.
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PMID:p21WAF1-derived peptides linked to an internalization peptide inhibit human cancer cell growth. 910 43


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