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

The pancreatic cell line beta TC1, established from insulinomas of transgenic mice carrying a hybrid insulin-promoted large T antigen gene, has retained several characteristics of normal cells, including the insulin content and inducibility of insulin secreting by glucose. We show here that the growth of beta TC1 cells is arrested in low serum-concentration medium. Cells exposed for three days to 0.25% fetal calf serum ceased to incorporate [3H]thymidine but were still able to resume the cell division cycle upon addition of serum. In this cell line, we have determined by cytofluorometry the cell cycle kinetic parameters to be of 21 h, 10 h 30 min and 12 h for the G1, S and G2/M phases, respectively. Quiescent beta TC1 cells constitutively expressed the protooncogene c-jun that codes for the transcriptional factor AP1, as well as cdc2, another cell cycle-related gene. A large transient increase in the expression of the c-fos gene was obtained rapidly, 30 min after addition of serum and a similar increase in c-jun expression after one hour. Expression of the cdc2 gene was also enhanced to a lesser extent. The same effects were also observed in the presence of cycloheximide, thus proving that the expression of these three genes is directly stimulated by serum growth factors. Consequently, quiescent beta TC1 cells provide a good model for studying the short- and long-term effects of growth factors on Beta-cell proliferation.
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PMID:Cell cycle and gene expression in the insulin producing pancreatic cell line beta TC1. 170 44

Shionogi Carcinoma 115 (SC 115) cells are a cloned cell line derived from androgen-dependent mouse mammary tumor. They can grow in serum-free culture if a physiological level of androgen is present in the medium, but can not proliferate in culture without testosterone. In the present study, the mechanism of cell death in SC 115 cells after androgen withdrawal was examined. Based upon the temporal sequence of DNA fragmentation, morphologic changes and loss of cell viability, androgen withdrawal induces programmed cell death (apoptosis) of SC 115 cells in serum-free culture. Northern blot analysis was used to identify a series of genes whose expression per cell is enhanced during the recruitment of cells from a nonproliferative (i.e. G0) state into G1 (i.e.,cyclins D1 and C), from G1 into the S phase of the cell cycle (i.e., cdk2), and during the programmed cell death pathway (i.e. testosterone repressed prostatic message-2 (TRPM-2), transforming growth factor-beta1 (TGF-beta1) and glucose regulated 78 kilodalton protein (GRP-78). Expression of TRPM-2, TGF-beta1, GRP-78, and calmodulin genes increases, but that of cyclins C and D1, and cdk2 genes decreases during programmed cell death of SC 115 cells. These results demonstrate that androgen-dependent SC 115 cells undergo programmed cell death induced by androgen withdrawal, and that this death does not require proliferation or progression into G1 of the proliferative cell cycle. SC 115 cells should be a good model for investigating programmed death of hormone-dependent cancer.
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PMID:Induction of programmed death/apoptosis androgen-dependent mouse mammary tumor cell line (Shionogi Carcinoma 115) by androgen withdrawal. 863 4

Glucose-regulated stress response of cancer cells occurs during the growth of solid tumors and is induced in culture by treatments with various agents, including 2-deoxyglucose, glucosamine, and calcium ionophore A23187. We previously reported that the three stressors commonly induced cell-cycle arrest in the G1 phase and resistance to antitumor drugs in human cancer A2780 and HT-29 cells. In this study, we investigated the mechanisms of stress-induced G1 arrest by determining the expression of cell-cycle-regulating proteins. Among G1 cyclins and cyclin-dependent kinases (cdk) examined, the expression levels of cyclin D1 preferentially decreased in the stressed cells. A time-course study showed that the decrease in cyclin D1 coincided with the appearance of hypophosphorylated retinoblastoma protein (pRb), which is the growth suppressive form. These findings suggest that the stress-induced G1 arrest is mediated through the down-regulation of cyclin D1-associated kinases (cdk4/6), pRb kinases during G1 phase. This was also supported by decreased cdk4 expression in stressed HT-29 cells. In addition, p21WAF1, a cdk inhibitor, was induced in the stressed cells, particularly A23187-treated cells. A23187, compared with the other stressors, caused extreme pRb hypophosphorylation, suggesting that p21WAf1 is involved in the regulation of pRb phosphorylation in the stressed cells. Our present findings could explain a molecular-based mechanism of a growth-arrested quiescent state and also resistance to chemotherapy of solid tumor cells.
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PMID:Glucose-regulated stresses cause decreased expression of cyclin D1 and hypophosphorylation of retinoblastoma protein in human cancer cells. 900 Jan 44

Transforming growth factor-beta (TGF-beta) may mediate high glucose effects in renal cells. Thus, Madin-Darby canine kidney cells were studied for the modulation of cell cycle regulatory proteins by high glucose (27.5 mM) and TGF-beta1. We showed that unlike other renal cells, TGF-beta1 mRNA and its bioactivity were not induced by high-glucose culture. Furthermore, high glucose per se increased cellular proliferation without alterations in cell size. High glucose also increased the percentage of cells in the G2/M phase while decreasing cells in the G0/G1 phase of the cell cycle. In contrast, TGF-beta1 dose dependently (1 to 4 ng/ml) decreased cellular mitogenesis while increasing hypertrophy in the cells, especially in the presence of high glucose. TGF-beta1 also increased the percentage of cells arrested in the G0/G1 phase while decreasing cells in the G2/M phase of the cell cycle. Regarding two of the cell cycle regulatory proteins, high glucose increased cdc2 kinase activity and retinoblastoma protein (pRb) phosphorylation. In contrast, TGF-beta1 decreased cdc2 kinase activity and pRb phosphorylation, especially in the presence of high glucose. Additionally, glucose dose dependently (5.5, 16.5, 27.5, and 38.5 mM) increased type I and II TGF-beta receptor protein expression. In conclusion, changes in cdc2 kinase activity and pRb phosphorylation were correlated with high glucose and TGF-beta1-induced growth effects in a cell cycle-dependent manner in the Madin-Darby canine kidney cells. Furthermore, high glucose may potentiate TGF-beta1-induced effects by enhancing TGF-beta receptor protein expression.
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PMID:Interaction between high glucose and TGF-beta in cell cycle protein regulations in MDCK cells. 952 94

Early diabetic nephropathy is characterized by glomerular hypertrophy. Previous studies in vitro have demonstrated that mesangial cells exposed to high glucose are arrested in the G1-phase of the cell cycle and express increased levels of the cyclin-dependent kinase inhibitor p27Kip1. The present study was performed to investigate the renal expression of p27Kip1 in db/db mice, a model of diabetes mellitus type II. Glomerular p27Kip1 protein, but not mRNA expression, was strongly enhanced in diabetic db/db mice compared with non-diabetic db/+ littermates. Immunohistochemical studies revealed that this stimulated expression was mainly restricted to the nuclei of mesangial cells and podocytes, but glomerular endothelial cells occasionally also stained positively. Quantification of p27Kip1 positive glomerular cells showed a significant increase of these cells in db/db mice compared with non-diabetic db/+ animals. Although tubular cells revealed a positive staining for p27Kip1 protein, there was no difference between db/+ and db/db mice. Immunoprecipitation experiments revealed that p27Kip1 protein associates with Cdk2 and Cdk4, but not with Cdk6. To test for the influence of hyperglycemia on cell cycle arrest and p27Kip1 expression, mesangial cells were isolated from db/+ and db/db mice. There was a similar basal proliferation when these cells were grown in normal glucose-containing medium (100 mg/dl). However, raising the glucose concentration to 275 to 450 mg/dl induced cell cycle arrest in db/+ as well as db/db mesangial cells. Increasing the medium osmolarity with D-mannitol failed to induce p27Kip1 expression in mesangial cells. Transfection of cells with p27Kip1 antisense, but not missense, phosphorothioate oligonucleotides facilitated cell cycle progression equally well in db/+ and db/db mesangial cells. Furthermore, p27Kip1 expression was comparable in both cell lines in normal glucose, but increased in high glucose medium. Our studies demonstrate that p27Kip1 expression is enhanced in diabetic db/db animals. This induction appears to be due to hyperglycemia. Expression of p27Kip1 may be important in cell cycle arrest and hypertrophy of mesangial cells during early diabetic nephropathy.
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PMID:Glomerular expression of p27Kip1 in diabetic db/db mouse: role of hyperglycemia. 955 93

Skp1 interacts with cullins, F-box containing proteins, and forms a complex with cyclin A-Cdk2 in mammalian cells. Skp1 is also involved in diverse biological processes like degradation of key cell cycle regulators, glucose sensing, and kinetochore function. However, little is known about the structure and exact function of Skp1. Here we characterized the interaction between Skp1 and the F-box protein Skp2. We show that Skp1 can bind to Skp2 in vitro using recombinant proteins, and in vivo using the yeast two-hybrid system. Deletion analysis of Skp1 indicated that most of the Skp1 protein is required for binding to Skp2. In mammalian cell extracts, a large portion of Skp1 appears to associate with proteins other than Skp2. Biochemical analysis indicated that Skp1 is likely to be a flexible, non-spherical protein, and is capable of forming dimers.
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PMID:Characterization of the cullin and F-box protein partner Skp1. 982 42

The lethal toxin (LT) from Clostridium sordellii is a glucosyltransferase that modifies and inhibits small G proteins of the Ras family, Ras and Rap, as well as Rac proteins. LT induces cdc2 kinase activation and germinal vesicle breakdown (GVBD) when microinjected into full-grown Xenopus oocytes. Toxin B from Clostridium difficile, that glucosylates and inactivates Rac proteins, does not induce cdc2 activation, indicating that proteins of the Ras family, Ras and/or Rap, negatively regulate cdc2 kinase activation in Xenopus oocyte. In oocyte extracts, LT catalyzes the incorporation of [14C]glucose into a group of proteins of 23 kDa and into one protein of 27 kDa. The 23-kDa proteins are recognized by anti-Rap1 and anti-Rap2 antibodies, whereas the 27-kDa protein is recognized by several anti-Ras antibodies and probably corresponds to K-Ras. Microinjection of LT into oocytes together with UDP-[14C]glucose results in a glucosylation pattern similar to the in vitro glucosylation, indicating that the 23- and 27-kDa proteins are in vivo substrates of LT. In vivo time-course analysis reveals that the 27-kDa protein glucosylation is completed within 2 h, well before cdc2 kinase activation, whereas the 23-kDa proteins are partially glucosylated at GVBD. This observation suggests that the 27-kDa Ras protein could be the in vivo target of LT allowing cdc2 kinase activation. Interestingly, inactivation of Ras proteins does not prevent the phosphorylation of c-Raf1 and the activation of MAP kinase that occurs normally around GVBD.
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PMID:Inhibition of small G proteins by clostridium sordellii lethal toxin activates cdc2 and MAP kinase in Xenopus oocytes. 988 92

The pathogenesis of diabetic neuropathy remains unclear, although several factors have been implicated in its pathogenesis. We have examined possible roles of decreased production of nitric oxide, ion channel dysfunction and decreased capacity of nerve regeneration. STZ-induced diabetic rats showed decreases in nociceptive threshold and NADPH-diaphorase positive neurons, nNOS level and cGMP content of DRG at 12 weeks after induction of diabetes. The rats injected by L-NAME, potent nNOS inhibitor, showed decreased nociceptive threshold, although D-NAME, inactive in nNOS inhibition, did not. These results suggest that decreased NO production might be involved in hyperalgesia in diabetic rats. Both hyperglycemia and decreased Na/K-ATPase activity are thought to be characteristic features of diabetic neuropathy. To investigate the presence of ion channel abnormality in diabetic nerves, a Vaseline-gap voltage clamp technique was applied for a single myelinated fibers under 30 mM high glucose plus 0.1 mM ouabain. Since K current was increased, a Ca activated K channel blocker was applied and this increase was shown to be suppressed. Furthermore, Ca channel blockers all suppressed increased K currents, suggesting that the condition induced an increase of Ca influx, thereby increasing Ca activated K currents through K channels. The data are important in that diabetic condition may induce both Ca influx, leading to nerve degeneration, and increased K current, resulting in decreased nerve conduction. Nerve regeneration has been known to be disturbed in diabetic condition. We have shown a decrease in nerve elongation rate in diabetic rats after crush of sciatic nerve, although this decrease was not ameliorated by ARI. Furthermore, Wallerian degeneration was shown to be delayed in diabetic nerves, leading to delayed nerve regeneration. Hyperphosphorylation of both medium and high molecular weight neurofilaments that might be induced by protein kinases including CDK 5 may be involved in the mechanism.
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PMID:[New trend in pathogenesis of diabetic neuropathy]. 1037 17

After mild ischemic insults, many neurons undergo delayed neuronal death. Aberrant activation of the cell cycle machinery is thought to contribute to apoptosis in various conditions including ischemia. We demonstrate that loss of endogenous cyclin-dependent kinase (Cdk) inhibitor p16(INK4a) is an early and reliable indicator of delayed neuronal death in striatal neurons after mild cerebral ischemia in vivo. Loss of p27(Kip1), another Cdk inhibitor, precedes cell death in neocortical neurons subjected to oxygen-glucose deprivation in vitro. The loss of Cdk inhibitors is followed by upregulation of cyclin D1, activation of Cdk2, and subsequent cytoskeletal disintegration. Most neurons undergo cell death before entering S-phase, albeit a small number ( approximately 1%) do progress to the S-phase before their death. Treatment with Cdk inhibitors significantly reduces cell death in vitro. These results show that alteration of cell cycle regulatory mechanisms is a prelude to delayed neuronal death in focal cerebral ischemia and that pharmacological interventions aimed at neuroprotection may be usefully directed at cell cycle regulatory mechanisms.
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PMID:Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death. 1143 80

In Aspergillus nidulans, germinating conidia undergo multiple rounds of nuclear division before forming a septum. Previous genetic results suggest that the ability to separate nuclear division and septum formation depends upon a threshold level of activity of the cyclin-dependent kinase NIMX(cdk1). Mutations in nimX and nimT, the gene encoding the NIMX(cdk1)-activating phosphatase, have revealed that Tyr-15 phosphorylation is important for determining the timing of the formation of the first septum. Here, we describe a screen for suppressors of nimT23 (snt), designed to identify additional components of the pathway regulating septum formation. We show that a subset of the snt mutants are defective in the temporal regulation of septum formation and in cell cycle checkpoint responses. Molecular characterization of sntA shows that it is allelic to the previously described ankA gene, which encodes the NIMX(cdk1) Tyr-15 kinase. Additional experiments described in this study show that nutritional conditions modulate the timing of septum formation and alter the phenotypes displayed by the snt mutants. A model that suggests that the timing of septum formation is influenced by DNA damage and glucose availability via the sntA and sntB gene products is proposed.
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PMID:The Aspergillus nidulans snt genes are required for the regulation of septum formation and cell cycle checkpoints. 1160 33


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