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)

Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8) is a novel gammaherpesvirus implicated in the cause of Kaposi's sarcoma and certain malignancies of lymphatic origin. One of the candidate genes possibly involved in promoting tumor development is an open reading frame (ORF) with sequence similarity to human type D cyclin genes. This cyclin-like gene, when expressed in tissue culture cells, promotes phosphorylation and inactivation of the retinoblastoma tumor suppressor protein and thereby may result in deregulation of cell division control. We report here the biochemical characterization of this cyclin (KSHV-cyc) and the kinase activity that it elicits upon expression in tissue culture cells. We demonstrate that the kinase activity associated with KSHV-cyc is sensitive to the cdk inhibitor p27 (KIP) and due to activation of cdk6. However, in contrast to cdk6 activated by cellular type D cyclins, the cdk6 activated by KSHV-cyc is capable of phosphorylating not only the retinoblastoma protein but also histone H1. This finding implies that activation by KSHV-cyc alters the substrate preference of this cdk. This may have important physiological consequences in that the kinase activity triggered by this viral cyclin may abrogate cell cycle checkpoints in addition to those targeted by cellular cyclin D-cdk6 kinase.
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PMID:The cyclin encoded by Kaposi's sarcoma-associated herpesvirus stimulates cdk6 to phosphorylate the retinoblastoma protein and histone H1. 915 5

Interferon gamma (IFNgamma) induces growth arrest in normal human mammary epithelial cells by establishing a block during mid-G1 corresponding to the time when the retinoblastoma protein (Rb) would normally be inactivated by hyperphosphorylation. IFNgamma inhibits the kinase activities of cdk2, cdk4 and cdk6 within 24 h of treatment. Protein levels of the cdks and G1 cyclins do not change within this time period, although cdk4 levels are significantly reduced by 48 h. IFNgamma treatment induces p27Kip1 protein levels, presumably by a post-transcriptional mechanism as no change was observed in the mRNA levels. In addition, IFNgamma-induced inhibition of cdk2 and cyclin E-associated kinase activities is accompanied by a 4.5-fold or greater increase of p27Kip1 in cdk2 complexes. p27 may also have a role in the inhibition of cdk4/6 kinase activities, as p27 protein associated with these complexes was increase by 55-70% after IFNgamma. In mammary carcinoma cell lines which are resistant to growth inhibition by IFNgamma, p27 levels are not induced by IFNgamma nor is cdk2 kinase activity inhibited, despite high baseline levels of p27 in cdk2 complexes. However, exogenous expression of p27 in these cells induces growth arrest. In addition, purified p27 protein added to cdk2 complexes immunoprecipitated from carcinoma cells is able to inhibit the kinase activity in a dose dependent manner. Our results suggest that p27Kip1 has a role in mediating IFNgamma-induced terminal growth arrest. Resistance of mammary carcinomas to growth inhibition by IFNgamma does not appear to involve resistance of cdk2 complexes to the action of p27, but rather an inability to appropriately regulate the balance of cdk2, cyclin E and p27 levels.
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PMID:The role of p27Kip1 in gamma interferon-mediated growth arrest of mammary epithelial cells and related defects in mammary carcinoma cells. 916 Aug 91

In order to elucidate the biochemical mechanisms by which the universal cyclin kinase inhibitor p27Kip1 regulates cell cycle progression in human breast cancer cells, a recombinant adenovirus expressing human p27 was constructed (Adp27). Upon infection of human breast cancer cells MDA-MB-231 and MCF-7 with Adp27, a high level of p27 expression was observed, and this resulted in a marked decrease in the proportion of cells in S-phase. In multiple cell lines, comparison of the cytotoxicity of Adp27 with another adenovirus vector expressing the related universal cyclin kinase inhibitor WAF1/Cip1 (AdWAF1), showed Adp27 to be markedly more (up to 56-fold) toxic than AdWAF1. DNA histograms showed Adp27 to cause a G1/S arrest at lower viral doses than AdWAF1. Analysis of cyclin dependent kinase activity following Adp27 infections showed decreased Cdk2 and cyclin B1-Cdc2 activity at lower viral doses when compared with AdWAF1. Adp27 is therefore potentially useful for studies of growth regulation and for gene therapy when growth inhibition is desired.
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PMID:A recombinant adenovirus expressing p27Kip1 induces cell cycle arrest and loss of cyclin-Cdk activity in human breast cancer cells. 917 4

Induction of the Myc-oestrogen receptor fusion protein (MycER) by 4-OH-tamoxifen (OHT) leads to the activation of Cyclin E/Cyclin-dependent kinase 2 (CycE/Cdk2) complexes followed by the induction of DNA synthesis. As CycE/Cdk2 activity is essential for G1/S transition, we have investigated the mechanism by which Myc can activiate CycE/Cdk2. Our results suggest that this activation may involve at least two Myc-dependent steps: the induction of cyclin E gene transcription followed by accumulation of cyclin E mRNA in a protein synthesis-independent manner and the inhibition of p27(Kip1) association with CycE/Cdk2 complexes containing newly synthesised CycE. As a consequence phosphorylation of CycE-bound Cdk2 by cyclin activating kinase (CAK) is accelerated. We propose a model in which the active newly synthesised CycE/Cdk2 complexes trigger a positive feed-back mechanism to activate preexisting complexes through phosphorylation-dependent p27(Kip1) release.
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PMID:Myc activation of cyclin E/Cdk2 kinase involves induction of cyclin E gene transcription and inhibition of p27(Kip1) binding to newly formed complexes. 918 52

CDK inhibitors are thought to prevent cell proliferation by negatively regulating cyclin-CDK complexes. We propose that the opposite is also true, that cyclin-CDK complexes in mammmalian cells can promote cell cycle progression by directly down-regulating CDK inhibitors. We show that expression of cyclin E-CDK2 in murine fibroblasts causes phosphorylation of the CDK inhibitor p27Kip1 on T187, and that cyclin E-CDK2 can directly phosphorylate p27 T187 in vitro. We further show that cyclin E-CDK2-dependent phosphorylation of p27 results in elimination of p27 from the cell, allowing cells to transit from G1 to S phase. Moreover, mutation of T187 in p27 to alanine creates a p27 protein that causes a G1 block resistant to cyclin E and whose level of expression is not modulated by cyclin E. A kinetic analysis of the interaction between p27 and cyclin E-CDK2 explains how p27 can be regulated by the same enzyme it targets for inhibition. We show that p27 interacts with cyclin E-CDK2 in at least two distinct ways: one resulting in p27 phosphorylation and release, the other in tight binding and cyclin E-CDK2 inhibition. The binding of ATP to the CDK governs which state predominates. At low ATP (< 50 microM) p27 is primarily a CDK inhibitor, but at ATP concentrations approaching physiological levels (> 1 mM) p27 is more likely to be a substrate. Thus, we have identified p27 as a biologically relevant cyclin E-CDK2 substrate, demonstrated the physiological consequences of p27 phosphorylation, and developed a kinetic model to explain how p27 can be both an inhibitor and a substrate of cyclin E-CDK2.
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PMID:Cyclin E-CDK2 is a regulator of p27Kip1. 919 73

In order to elucidate the mechanisms by which estrogens and antiestrogens modulate the growth of breast cancer cells, we have characterized the changes induced by estradiol that occur during the G1 phase of the cell cycle of MCF-7 human mammary carcinoma cells. Addition of estradiol relieves the cell cycle block created by tamoxifen treatment, leading to marked activation of cyclin E-cdk2 complexes and phosphorylation of the retinoblastoma protein within 6 h. Cyclin D1 levels increase significantly while the levels of cyclin E, cdk2, and the p21 and p27 cdk inhibitors are relatively constant. However, the p21 cdk inhibitor shifts from its association with cyclin E-cdk2 to cyclin D1-cdk4, providing an explanation for the observed activation of the cyclin E-cdk2 complexes. These results support the notion that cyclin D1 has an important role in steroid-dependent cell proliferation and that estrogen, by regulating the activities of G1 cyclin-dependent kinases, can control the proliferation of breast cancer cells.
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PMID:Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution. 919 41

IL-4 is a pleiotrophic cytokine that has been shown to affect cells of the central nervous system. We have demonstrated that IL-4 inhibits DNA synthesis and proliferation in human astroglia expressing IL-4 receptors. In this study, we sought to identify mechanisms that could account for the antimitogenic effects of IL-4. Epidermal growth factor (EGF)-stimulated human astroglia were arrested in G1 phase by IL-4, even though IL-4 stimulated levels of the G1 cyclins, D1 and E. Histone H1 kinase activity of cdk2 immunoprecipitates, however, was sharply reduced by IL-4; impairment of kinase activity was also evident in cyclin E immunoprecipitates, which contained evidence of hypophosphorylated (inactive) cdk2 product. Reduced cyclin E-associated cdk2 activity was not due to impaired cyclin-dependent kinase-activating kinase (CAK) activity, which was unaffected by IL-4. Inactive cyclin E/cdk2 complexes from IL-4 + EGF-treated cells contained, however, strikingly elevated p27Kip1 cdk inhibitor. Elevated p27 was also detectable in whole cell lysates after 24 and 48 h of IL-4 treatment; by 72 h, p27 was no longer elevated. Pretreatment with antisense but not mismatch p27 oligonucleotides attenuated the inhibitory effects of IL-4 on DNA synthesis and histone kinase activity of cyclin E/cdk2 complexes. Antisense p27 also abrogated IL-4-mediated elevation of p27 in whole cell lysates and cyclin E/cdk2 complexes. These findings demonstrate that IL-4 regulates the cell cycle machinery of astroglial cells via a p27Kip1 braking mechanism.
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PMID:The CDK inhibitor, p27Kip1, is required for IL-4 regulation of astrocyte proliferation. 921 99

Cyclin-dependent kinase (Cdk) inhibitors play significant roles in the cell cycle control of various biological phenomena. To characterize the role of Cdk inhibitors in rat cells, we isolated a cDNA encoding rat p27Kip1, a 27-kDa Cdk inhibitor. The 1.04-kb cDNA of rat p27 contained an open reading frame of 197 amino acids that shared high homology with mammalian p27 and significant homology with mammalian p21Cip1 and p57Kip2. p27 mRNA was detected in most rat tissues and cell lines. The levels of p27 protein expression were similar in rat cell lines transformed by E1A and in normal cells. Rat p27 was able to interact with Cdk 2/4 and cyclin A/D in rat cells, but the amounts of rat p27 in Cdk2 complexes were different between transformed cells and normal cells. Thus, the formation of stable complexes of rat p27 may be modulated by E1A. Rat p27 protein could inhibit the increased Cdk2-associated kinase activity in transformed rat cells.
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PMID:Cloning and characterization of rat p27Kip1, a cyclin-dependent kinase inhibitor. 921 22

Control of cell proliferation remains of intense interest in cancer research. In the 1,25-dihydroxyvitamin D3 HL60 cell system, G1 arrest has been shown to be mediated by elevated levels of p27/Kip1 protein. We show here that the main target of the elevated p27/Kip1 in this system is cyclin-dependent kinase (Cdk) 6. The activity of Cdk2 is also down-regulated, and this is associated with altered and reduced levels of cyclin E in the kinase complex. Paradoxically, the kinase activity of Cdk4 is elevated, in spite of an almost complete G1 block. These data show that the functions of Cdk4 and Cdk6 are not redundant and that Cdk6 and Cdk2 activities are regulated by 1,25-dihydroxyvitamin D3.
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PMID:Cyclin-dependent kinase 6 is the principal target of p27/Kip1 regulation of the G1-phase traverse in 1,25-dihydroxyvitamin D3-treated HL60 cells. 923 Jan 88

Cdc25A, a phosphatase essential for G1-S transition, associates with, dephosphorylates, and activates the cell cycle kinase cyclin E-cdk2. p21CIP1 and p27 are cyclin-dependent kinase (cdk) inhibitors induced by growth-suppressive signals such as p53 and transforming growth factor beta (TGF-beta). We have identified a cyclin binding motif near the N terminus of Cdc25A that is similar to the cyclin binding Cy (or RR LFG) motif of the p21CIP1 family of cdk inhibitors and separate from the catalytic domain. Mutations in this motif disrupt the association of Cdc25A with cyclin E- or cyclin A-cdk2 in vitro and in vivo and selectively interfere with the dephosphorylation of cyclin E-cdk2. A peptide based on the Cy motif of p21 competitively disrupts the association of Cdc25A with cyclin-cdks and inhibits the dephosphorylation of the kinase. p21 inhibits Cdc25A-cyclin-cdk2 association and the dephosphorylation of cdk2. Conversely, Cdc25A, which is itself an oncogene up-regulated by the Myc oncogene, associates with cyclin-cdk and protects it from inhibition by p21. Cdc25A also protects DNA replication in Xenopus egg extracts from inhibition by p21. These results describe a mechanism by which the Myc- or Cdc25A-induced oncogenic and p53- or TGF-beta-induced growth-suppressive pathways counterbalance each other by competing for cyclin-cdks.
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PMID:p21CIP1 and Cdc25A: competition between an inhibitor and an activator of cyclin-dependent kinases. 923 91


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