Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rapamycin, a bacterial macrolide antibiotic, is a potent immunosuppressant agent that blocks cell proliferation by inhibiting the G1/S transition in several cell types. In sensitive cells, rapamycin inhibits the phosphorylation of p70 S6K and of Rb; however, the precise mechanisms involved have not been elucidated. In the mouse BP-A31 fibroblasts, synchronised in G0/G1 phase by serum starvation and induced to reinitiate the G1-phase progression, rapamycin inhibited the entry into S phase. The effect of rapamycin was situated in early G1 phase. The assembly of the cyclin D1/cdk4 complexes that phosphorylate Rb early in the G1 phase was not modified by the drug. Nevertheless, an inhibition of the activation of cyclin D1/cdk4 and cyclin E/cdk2 as well as of Rb phosphorylation accompanied the cell cycle arrest. Remarkably, rapamycin reduced the level of total p21(WAF1/CIP1) as well as that of p21(WAF1/CIP1) associated with the cyclin D1/cdk4 complexes. Besides its inhibitory activity toward cdk, p21(WAF1/CIP1) has been recently found to participate in the formation/stabilisation/nuclear translocation of cyclin D1/cdk4 complexes. We propose that the inhibition of the expression of p21(WAF1/CIP1) is a mechanism by which rapamycin inhibits the triggering of the cdk cascade in the BP-A31 cells.
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PMID:Rapamycin inhibits cdk4 activation, p 21(WAF1/CIP1) expression and G1-phase progression in transformed mouse fibroblasts. 1463 3

E1A + c-Ha-ras-transformants overexpressing bcl-2 oncogene are able to be arrested at the G1/S boundary of the cell cycle after DNA damage and upon serum starvation, this cell cycle blockage being accompanied by a decrease in the activity of cyclin E--Cdk2 complexes. Roscovitine-induced inhibition of cyclin-dependent kinases (Cdks) activity does not result in the G1/S arrest of E1A + c-Ha-ras + bcl-2-transformants. Roscovitine treatment causes an accumulation of G2/M cells, mainly at the expense of mitotic cells. However, the expression of Bcl-2 oncoproducts does not re-establish the regulation of mitotic events broken by introduction of E1A and c-Ha-ras oncogenes in normal cells, as revealed by the treatment of E1A + c-Ha-ras + bcl-2-transformants with nocodazole inducing mitotic arrest in normal cells. In spite of the elevated expression of antiapoptotic bcl-2 gene in transformants, nocodazole treatment results in mass apoptotic death preceded by polyploidy. Roscovitine also induces apoptosis with no polyploid cell accumulation being observed. Inhibition of Cdks activity with Roscovitine, as well as violation of microtubule depolymerization with nocodazole result in the apoptotic death in the tested cell lines sensitive (E1A + c-Ha-ras) and resistant (E1A + c-Ha-ras + bcl-2) to damaging agents. Thus, the application of Roscovitine, a specific inhibitor of Cdks, suggests that the decrease in Cdks activity in E1A + c-Ha-ras + bcl-2-transformants is not likely to be responsible for G1/S cell cycle arrest realization after damaging influences. Moreover, an antiproliferative effect of Bcl-2 in E1A + c-Ha-ras-transformants is restricted by restoration of cell cycle events at G1/S and G2/M boundaries, and does not concern the program of mitotic events regulation.
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PMID:[Antiproliferative effect of bcl-2 gene does not concern the control of mitotic events]. 1521 71

Fetal growth retardation, a common end point for a variety of conditions affecting mother and fetus, is associated with reduced liver mass. We have performed studies to determine the mechanism for decreased liver mass in a maternal starvation model of fetal growth restriction in the rat. Pregnant dams were deprived of food for 48 h before delivery on embryonic day 19 (E19). Fetal body weight was not affected. However, fetal liver weight was reduced by approximately 15%. Immunostaining of fetal liver for proliferating cell nuclear antigen and flow cytometry on isolated fetal hepatocytes showed G1 cell cycle arrest in samples from starved dams. Based on our prior studies showing attenuated hepatic insulin signaling in the late gestation fetal rat, we tested the hypothesis that G1 arrest in our model might be due to altered nutrient signaling. Fetal plasma amino acid analyses showed no decrease in branched-chain amino acids, but arginine concentrations were decreased in fetuses of fasted mothers. Reduced arginine in E19 fetal hepatocyte culture media was associated with decreased DNA synthesis. Whereas levels of cyclins D and E were unchanged in fetal hepatocytes exposed to low arginine, cyclin E-dependent kinase activity was reduced. Low arginine also induced changes in the translational machinery, indicative of impaired signaling through the nutrient sensing kinase mammalian target of rapamycin. Our results are consistent with the hypothesis that restricted nutrient availability signals to the hepatocyte cell cycle in fetuses of fasted mothers, thereby accounting for decreased hepatocyte proliferation and liver mass.
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PMID:Effects of maternal starvation on hepatocyte proliferation in the late gestation fetal rat. 1561 45

Ribonucleoside diphosphate reductase (EC 1.17.4.1) (RR) is a potential target for antineoplastic agents due to its crucial role in DNA replication and repair. The expression and activity of RR subunits are highly regulated to maintain an optimal dNTP pool, which is required to maintain genetic fidelity. The human RR small subunit M2B (p53R2) is thought to contribute to DNA repair in response to DNA damage. However, it is not clear whether M2B is involved in providing dNTPs for DNA replication under physiological growth conditions. Serum starvation synchronized studies showed that a rapid increase of M2B was associated with cyclin E, which is responsible for regulation of G(1)/S-phase transition. A living cell sorting study that used KB cells in normal growth, further confirmed that M2B increased to maximum levels at the G(1)/S-phase transition, and decreased with DNA synthesis. Confocal studies revealed that M2B redistributed from the cytoplasm to the nucleus earlier than hRRM2 in response to DNA replication. Nuclear accumulation of M2B is associated with dynamic changes in dNTP at early periods of serum addition. By using M2B-shRNA expression vectors, inhibition of M2B may result in growth retardation in KB cells. We conclude that M2B may translocate from the cytoplasm into the nucleus and allow dNTPs to initiate DNA synthesis in KB cells under physiological conditions. Thus, our findings suggested that M2B might play an important role for initiating DNA replication of KB cells in normal growth.
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PMID:The ribonucleotide reductase subunit M2B subcellular localization and functional importance for DNA replication in physiological growth of KB cells. 1616 62

Protein kinase C (PKC) represents a family of serin/threonine kinases, playing a central role in the regulation of cell growth, differentiation and transformation. These enzymes differ in their primary structure, biochemical properties, tissue distribution and subcellular localization. The specific cellular functions of PKC isoforms are largely controlled by their localization. PKCeta, a member of the novel subfamily, is expressed predominantly in epithelial tissues. However, not much is known with respect to its mechanism of activation and regulation. Our recent studies suggest its role in cell cycle control. Here we show that PKCeta is localized at the Golgi apparatus, ER and the nuclear envelope. Furthermore, using GFP-fusion proteins of the different functional domains of PKCeta we deciphered the specific structural domains of the protein responsible for its apparent localization. We show that the cysteine-rich repeat C1b is responsible for its Golgi localization, while for its presence at the ER/nuclear envelope the pseudosubstrate containing fragment coupled to the C1 domain is required. In response to short-term activation by PMA we show translocation of PKCeta to the plasma membrane and the nuclear envelope. We demonstrate that the C1b is sufficient for its translocation to the plasma membrane. Interestingly, accumulation of PKCeta at the nuclear envelope also occurred in response to serum-starvation. It should be noted that interaction of PKCeta with the cyclin E/Cdk2 complex at the perinuclear region was recently reported by us in response to serum-starvation. Thus, our studies demonstrate translocation of PKCeta to the nuclear envelope, and suggest that the spatial regulation of PKCeta could be important for its cellular functions including effects on cell cycle control and involvement in tumor promotion.
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PMID:PKCeta is localized in the Golgi, ER and nuclear envelope and translocates to the nuclear envelope upon PMA activation and serum-starvation: C1b domain and the pseudosubstrate containing fragment target PKCeta to the Golgi and the nuclear envelope. 1624 15

Preclinical studies were performed of a novel selective imidazopyridine cyclin-dependent kinase (cdk) inhibitor, AZ703. In vitro kinase assays showed that IC50 values for AZ703 against purified cyclin E/cdk2 and cyclin B/cdk1 were 34 and 29 nmol/L, respectively. In contrast, the IC50 against cdk4 was 10 micromol/L. AZ703 also inhibited cdk7 and cdk9 with IC50 values of 2.1 micromol/L and 521 nmol/L, respectively. Treatment of U2OS, NCI-H1299, and A549 cells for 24 hours resulted in growth arrest involving multiple cell cycle phases. At low drug concentrations (< 2 micromol/L), G2 arrest predominated, whereas at higher concentrations (> or = 2 micromol/L), S-G2 arrest was observed. When cells were synchronized in G1 by starvation and released into AZ703, a block in G1 occurred that was not evident in exponentially growing cells. Cell cycle arrest was associated with reduced phosphorylation of the retinoblastoma protein and p27(Kip1) at cdk2 phospho-sites. Following longer exposures, apoptosis was evident. Cells were further sensitized to AZ703 following recruitment to S phase by synchronization. Consistent with the inhibition of cdks during S and G2 that modulate the activity and stability of E2F-1, AZ703 treatment induced E2F-1 expression. In U2OS and NCI-H1299 cells engineered to inducibly express the dominant-negative mutant E2F-1 (1-374), expression of the mutant decreased AZ703-mediated apoptosis, indicating dependence on E2F-1 transcriptional targets. AZ703-induced apoptosis in NCI-H1299 cells was enhanced by small interfering RNA-mediated depletion of cdk9, which caused reduced levels of Mcl-1 and XIAP, suggesting that cdk2, cdk1, and cdk9 represent a rational subset of family members for drug targeting.
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PMID:AZ703, an imidazo[1,2-a]pyridine inhibitor of cyclin-dependent kinases 1 and 2, induces E2F-1-dependent apoptosis enhanced by depletion of cyclin-dependent kinase 9. 1639 59

Retinoblastoma protein (RB) acts as a tumor suppressor in many tissue types, by promoting cell arrest via E2F-mediated transcriptional repression. In addition to the aberrant forms of the RB gene found in different types of cancers, many viral oncoproteins including the simian virus 40 large T antigen target RB. However, cellular factors that inhibit RB function remain to be elucidated. Here, we report that RB interacts with the high mobility group protein A1 (HMGA1), a-non-histone architectural chromatin factor that is frequently overexpressed in cancer cells. HMGA1 binds the small pocket domain of RB, and competes with HDAC1. Subsequently, overexpression of HMGA1 abolishes the inhibitory effect of RB on E2F-activated transcription from the cyclin E promoter. Under serum starvation, T98G cells had been previously shown to be arrested in the G0 phase in an RB-mediated manner. The G0 phase was characterized by growth arrest and low levels of transcription, together with the hypophosphorylation of RB and the downregulation of HMGA1. In contrast, such serum-depleted G0 arrest was abrogated in T98G cells overexpressing HMGA1. The overexpressed HMGA1 was found to form complexes with cellular RB, suggesting that downregulation of HMGA1 is required for G0 arrest. There were no phenotypic changes in HMGA1-expressing T98G cells in the presence of serum, but the persistent expression of HMGA1 under serum starvation caused various nuclear abnormalities, which were similarly induced in T antigen-expressing T98G cells. Our present findings indicate that overexpression of HMGA1 disturbs RB-mediated cell arrest, suggesting a negative control of RB by HMGA1.
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PMID:High mobility group protein HMGA1 inhibits retinoblastoma protein-mediated cellular G0 arrest. 1787 62

Thymidylate synthase (TS) is the enzyme that catalyses the last step in de novo thymidylate synthesis. It is of interest clinically because it is an effective target for drugs such as 5-fluorouracil, often used in combination therapy. Despite a number of earlier reports indicating that TS is a cell cycle-dependent enzyme, this remains equivocal. Here, we show that in HCT116 cells synchronised by serum starvation, there is a clear dissociation between the expression of cyclin E (a well-characterised cell-cycle protein) and TS. Although both cyclin E and TS mRNA and protein increased during G(1), TS upregulation was delayed. Moreover, TS levels did not decrease following S-phase completion while cyclin E decreased sharply. Similarly, clear differences were seen between cyclin E and TS as asynchronously growing HCT116 cells were growth-inhibited by low-serum treatment. In contrast to previous reports using rodent cells, adenovirus-mediated over-expression of E2F1 and cyclin E in three human cell lines had no effect on TS. Cell-cycle progression was blocked by treatment of cells with pharmacological inhibitors of CDK2 and CDK4 and by ectopic expression of p16INK4A. Whereas CDK2 inhibition had no effect on TS levels, inhibition of CDK4 was associated with decreased TS protein levels. These results provide the first evidence that drugs targeting CDK4 may be useful with anti-TS drugs as combination therapy for cancer.
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PMID:Expression of thymidylate synthase in human cells is an early G(1) event regulated by CDK4 and p16INK4A but not E2F. 1792 72

Adenoviruses (Ads) with E1B55K mutations can selectively replicate in and destroy cancer cells. However, the mechanism of Ad-selective replication in tumor cells is not well characterized. We have shown previously that expression of several cell cycle-regulating genes is markedly affected by the Ad E1b gene in WI-38 human lung fibroblast cells (X. Rao, et al., Virology 350:418-428, 2006). In the current study, we show that the Ad E1B55K region is required to enhance cyclin E expression and that the failure to induce cyclin E overexpression due to E1B55K mutations prevents viral DNA from undergoing efficient replication in WI-38 cells, especially when the cells are arrested in the G(0) phase of the cell cycle by serum starvation. In contrast, cyclin E induction is less dependent on the function encoded in the E1B55K region in A549 and other cancer cells that are permissive for replication of E1B55K-mutated viruses, whether the cells are in the S phase or G(0) phase. The small interfering RNA that specifically inhibits cyclin E expression partially decreased viral replication. Our study provides evidence suggesting that E1B55K may be involved in cell cycle regulation that is important for efficient viral DNA replication and that cyclin E overexpression in cancer cells may be associated with the oncolytic replication of E1B55K-mutated viruses.
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PMID:Adenovirus E1B55K region is required to enhance cyclin E expression for efficient viral DNA replication. 1823 96

In the present study, we investigated the effects of manganese chloride (MnCl2) on cell cycle progression in A549 cells used as a model of Mn-induced lung toxicity. Cells were treated with various concentrations of MnCl2 (0, 0.01, 0.1, 0.5, 1.0 or 2.0 mM) for 24, 48 or 72 h. Cell proliferation was determined with MTT assay and mitotic index measurement and apoptosis was measured by flow cytometer. The results showed that MnCl2 inhibited A549 cells proliferation in a dose- and time-dependent manner, and induced apoptosis in A549 cells. When G0/G1 cells obtained by serum starvation were incubated with 0.5 mM of MnCl2 in the presence of 10% serum for several time intervals, the disruption of cell cycle progression was observed. The G0/G1 arrest was induced by MnCl2 treatment at 16 h and the arrest maintained for 8 h. Following the G0/G1 arrest, MnCl2 blocked the cells at S phase at 28 h and the S phase arrest maintained for at least 4 h. And moreover, proteasome inhibitor MG132 was able to prolong the duration of G0/G1 arrest induced by MnCl2 treatment. Results of western blotting assay revealed that cellular Cdk4, Cdk2 and phospho-Cdk2 (Thr160) levels decreased in manganese-treated cells at both 20 and 28 h. In addition, the decreasing of Cyclin A level and the increasing of p53 and WAF1/p21 were also induced by MnCl2 treatment at 20 h. The expression of Cyclin D1, Cyclin E and Cdc25A proteins was not altered in manganese-treated cells at both 20 and 28 h. Our results indicate that MnCl2 orderly induces G0/G1 and S phase arrest in A549 cells, the decreasing of Cdk4, Cdk2 and Cyclin A, and the increasing of p53 and Cdks inhibitor WAF1/p21 might be responsible for the G0/G1 arrest, and the decreasing of Cdk4 and Cdk2 levels for the S phase arrest.
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PMID:Manganese chloride-induced G0/G1 and S phase arrest in A549 cells. 1857 15


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