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)

Conditional overexpression of human cyclins B1, D1, and E was accomplished by using a synthetic cDNA expression system based on the Escherichia coli tetracycline repressor. After induction of these cyclins in asynchronous Rat-1 fibroblasts, a decrease in the length of the G1 interval was observed for cyclins D1 and E, consistent with an acceleration of the G1/S phase transition. We observed, in addition, a compensatory lengthening of S phase and G2 so that the mean cell cycle length in populations constitutively expressing these cyclins was unchanged relative to those of their uninduced counterparts. We found that expression of cyclin B1 had no effect on cell cycle dynamics, despite elevated levels of cyclin B-associated histone H1 kinase activity. Induction of cyclins D1 and E also accelerated entry into S phase for synchronized cultures emerging from quiescence. However, whereas cyclin E exerted a greater effect than cyclin D1 in asynchronous cycling cells, cyclin D1 conferred a greater effect upon stimulation from quiescence, suggesting a specific role for cyclin D1 in the G0-to-G1 transition. Overexpression of cyclins did not prevent cells from entering into quiescence upon serum starvation, although a slight delay in attainment of quiescence was observed for cells expressing either cyclin D1 or cyclin E. These results suggest that cyclins D1 and E are rate-limiting activators of the G1-to-S phase transition and that cyclin D1 might play a specialized role in facilitating emergence from quiescence.
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PMID:Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. 811 3

Recent studies have identified a family of proteins called cyclins that control cell cycle. Among these proteins, cyclin B synthesis and degradation are necessary and sufficient to cause a Xenopus egg cell-free system to oscillate between S and M. To understand the link between hormonal regulation of cell growth and the expression of B-type cyclins, we studied the effect of estradiol on cyclin B1 mRNA in a hormone-responsive breast cancer cell line, MCF-7. Cells were synchronized at G1 by isoleucine starvation, and estradiol was added along with the removal of cell cycle block. Flow cytometric analysis showed 81 +/- 7% cells in G1 after 30 h of isoleucine starvation. Significant population of cells progressed to S by 16 h after the addition of estradiol, whereas a comparable transition occurred in control cells by 36 h only. In cells progressing from G1-->S-->G2-->M under the influence of estradiol, there was a significant increase in cyclin B1 mRNA at 30 and 36 h, consistent with the accumulation of this cyclin in G2/M. In addition, we found that cyclin B1 mRNA degradation occurred early in G1, and this process was accelerated by estradiol. At 2 h after removal of the isoleucine block, there was a 40% reduction in the level of cyclin B1 mRNA in estradiol-treated cells compared to untreated controls. Cyclin B1 protein degradation followed a similar pattern, as determined by Western blots using a monoclonal anti-cyclin B1 antibody. Since previous studies suggested a polyamine pathway in the mechanism of action of estradiol, we questioned whether polyamines are important in controlling the level of cyclin B1 mRNA. Treatment of synchronized cells with the polyamine biosynthetic inhibitor, difluoromethylornithine attenuated cyclin B1 mRNA degradation in the presence of estradiol. This process was mostly reversed by exogenous putrescine and spermidine but not by putrescine homologues. Collectively, these data suggest that the mechanism of cell growth regulation by estradiol in MCF-7 cells includes alterations in cyclin B1 mRNA. Our data also indicate molecular pathways for the action of polyamines in estrogenic control of cell cycle.
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PMID:Regulation of cyclin B1 by estradiol and polyamines in MCF-7 breast cancer cells. 831 64

The state of cellular senescence is characterised by an irreversible arrest in the G1 phase of the cell cycle. It has previously been shown that three cell cycle genes, cyclin A, cyclin B and cdc2, are not expressed in senescent human fibroblasts. All three gene products have functions after S-phase entry, so that their suppression cannot explain the irreversible G1 arrest. Here, we report that the abundance of transcripts from two other cell cycle genes, cdk2 and cdk4, thought to act during G1-->S progression, is significantly diminished in senescent cells of the diploid human fibroblast line WI-38. Surprisingly, two other cyclins, D1 and E, behave in a completely different way, in that their expression is elevated in senescent cells, especially under conditions of serum starvation. Both the synthesis and the steady-state level of cyclin D1 protein were also found to be markedly higher in senescent cells (3- to 6-fold). Cyclins D1 and E are thus the first genes shown to be overexpressed or deregulated in senescent cells. It is tempting to speculate that this deregulation may be due to the absence, in senescent cells, of a regulatory loop that would normally control their expression. This is supported by our finding that cyclin E-associated kinase activity in senescent cells is reduced approx. 14-fold. Our data also suggest that the deregulated expression of cyclin D1 and E is not sufficient to drive senescent cells into DNA replication.
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PMID:Deregulation of cyclins D1 and E and suppression of cdk2 and cdk4 in senescent human fibroblasts. 836 Feb 68

PHO4, a transcription factor required for induction of the PHO5 gene in response to phosphate starvation, is phosphorylated by the PHO80-PHO85 cyclin-CDK (cyclin-dependent kinase) complex when yeast are grown in phosphate-rich medium. PHO4 was shown to be concentrated in the nucleus when yeast were starved for phosphate and was predominantly cytoplasmic when yeast were grown in phosphate-rich medium. The sites of phosphorylation on PHO4 were identified, and phosphorylation was shown to be required for full repression of PHO5 transcription when yeast were grown in high phosphate. Thus, phosphorylation of PHO4 by PHO80-PHO85 turns off PHO5 transcription by regulating the nuclear localization of PHO4.
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PMID:Regulation of PHO4 nuclear localization by the PHO80-PHO85 cyclin-CDK complex. 853 22

GATA-1, mainly expressed during erythroid differentiation, has been shown to regulate the genes specifically expressed in the late stages of erythropoiesis and to protect erythroid cells from apoptosis, suggesting that it might interfere with the cell cycle. By expressing the retrovirally transduced human GATA-1 cDNA in NIH3T3 fibroblasts, we have shown that GATA-1 alone was unable to transactivate its erythroid-specific target genes in these nonerythroid cells. However, GATA-1 expression had a dramatic effect on the proliferation of these fibroblasts. The cloning efficiency of the GATA-1-expressing fibroblasts was maintained but their S phase was greatly elongated and their G1 and G2/M phases were reduced, impairing substantially their proliferation. When cultured at low serum concentrations for 48 hours, GATA-1-expressing fibroblasts failed to accumulate in the G0/G1 phases but did not become serum independent. GATA-1-expressing fibroblasts expressed D1, A, and B1 cyclin mRNAs under conditions of serum starvation or at confluence, whereas these cyclin mRNAs were downregulated in the parental NIH3T3 cells cultured under the same conditions. Moreover, these effects of GATA-1 expression on proliferation were not limited to NIH3T3 cells, since different clones of hGATA-1 virus-infected FDCP-1 cells, a murine interleukin-3-dependent hematopoietic cell line, had a slower growth rate than control cells. Based on these data, we hypothesize that GATA-1 plays a role in the regulation of the cell cycle during terminal erythroid differentiation.
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PMID:Constitutive expression of GATA-1 interferes with the cell-cycle regulation. 861 96

AP435 dot, a nuclear dot-like structure that is recognized by a monoclonal antibody AP435 MAb and that seems to correlate with perinuclear intermediate filaments, was identified as a nuclear body by double immunofluorescent staining with AP435 MAb and the nuclear-body-specific antibody alphaSp100 or mAb 5E10. In T24 cells, nuclear bodies usually appear as small entities with an apparent diameter ranging from 0.2 to 0.7 microm, and several to 20 or more of them are present per nucleus. After long culture without a change in the medium, however, nuclear bodies disappeared while one or more large doughnut-shaped bodies appeared, which had apparent outer diameters of 0.7-1.8 microm. When the medium was changed or medium components were added, large bodies disappeared and many nuclear bodies of normal size reappeared within several hours. Large-body formation was not related to the arrest of DNA synthesis, as revealed by double labeling with AP435 MAb and anti-cyclin antibody. Among the medium components, only an amino acid mixture induced the change from large bodies to nuclear bodies. Large-body formation was also observed in long-cultured HeLa cells. These results suggest that nuclear bodies reversibly aggregate or reorganized to form large bodies upon amino acid(s) starvation.
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PMID:Reversible large-body formation from nuclear bodies upon amino acid(s) starvation in T24 cells. 861 7

Cdc2, a catalytic subunit of cyclin-dependent kinases, is required for both the G1-to-S and G2-to-M transitions in the fission yeast Schizosaccharomyces pombe. Cdc13, a B-type cyclin, is required for the M-phase induction function of Cd2. Two additional B-type cyclins, Cig1 and Cig2, have been identified in S. pombe, but none of the B-type cyclins are individually required for the onset of S. We report that Cdc13 is important for DNA replication in a strain lacking Cig2. Unlike deltacdc13 cells, double-mutant deltacdc13 deltacig2 cells are defective in undergoing multiple rounds of DNA replication. The conclusion that Cig2 promotes S is further supported by the finding that Cig2 protein and Cig2-associated kinase activity appear soon after the completion of M and peak during S, as well as the observation that S is delayed in deltacig2 cells as they recover from a G1 arrest induced by nitrogen starvation. These studies indicate that Cig2 is the primary S-phase-promoting cyclin in S. pombe but that Cdc13 can effectively substitute for Cig2 in deltacig2 cells. These observations also suggest that the gradual increase in the activity of Cdc2-Cdc13 kinase can be sufficient for the correct temporal ordering of S and M phases in deltacig2 cells.
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PMID:Cig2, a B-type cyclin, promotes the onset of S in Schizosaccharomyces pombe. 865 26

Saccharomyces cerevisiae cells treated with the immunosuppressant rapamycin or depleted for the targets of rapamycin TOR1 and TOR2 arrest growth in the early G1 phase of the cell cycle. Loss of TOR function also causes an early inhibition of translation initiation and induces several other physiological changes characteristic of starved cells entering stationary phase (G0). A G1 cyclin mRNA whose translational control is altered by substitution of the UBI4 5' leader region (UBI4 is normally translated under starvation conditions) suppresses the rapamycin-induced G1 arrest and confers starvation sensitivity. These results suggest that the block in translation initiation is a direct consequence of loss of TOR function and the cause of the G1 arrest. We propose that the TORs, two related phosphatidylinositol kinase homologues, are part of a novel signaling pathway that activates eIF-4E-dependent protein synthesis and, thereby, G1 progression in response to nutrient availability. Such a pathway may constitute a checkpoint that prevents early G1 progression and growth in the absence of nutrients.
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PMID:TOR controls translation initiation and early G1 progression in yeast. 2289 Oct 31

N3T3 and P-3T3 cells, originally isolated from a NIH3T3 cell clone on the basis of their negative and positive transformation by v-Abl, v-Src and Bcr-Abl, were previously found to show distinct cyclin activity changes following 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment, which is anti-mitogenic for N-3T3 cells and mitogenic for P-3T3 cells. We have found in this study that, while the G1/S arrest and cell death induced by serum starvation and TPA treatment in N-3T3 cells did not involve p53-mediated checkpoint or apoptosis, N-3T3 and P-3T3 cells evidently responded differently in these aspects of cell cycle regulation to DNA-damaging agents, methylmethane sulfonate (MMS) and gamma-radiation. In N-3T3 cells, DNA damages elicit cell growth arrest at G1/S transition with concomitant accumulation of p53 and p53-inducible Waf1/Cip1 proteins and also signs of apoptosis such as DNA ladder patterns and apoptotic (subgenomic) peak in flow cytograph. Conversely, P-3T3 cells treated with the DNA-damaging agents showed no cell cycle interruption nor accumulation of p53 or Waf1/Cip1. However, both P-3T3 and N-3T3 cells showed the same p53 protein half-life of 40 min or less, the same wild-type p53 DNA sequence and the same co-immunoprecipitable cellular proteins in complexes with p53, suggesting that an alteration in a signal transduction pathway upstream of p53 might account for the evasion of p53-mediated G1 checkpoint in P-3T3 cells.
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PMID:Distinct p53-mediated G1/S checkpoint responses in two NIH3T3 subclone cells following treatment with DNA-damaging agents. 876 Mar 4

Differentially regulated expression of activators and inhibitors of cyclin-dependent kinases (cdks) modulate cell cycle progression. In normal fibroblasts, these complexes consist of the cdk inhibitor p21WAF1/PCNA/G1 cyclin/cdk. We now show that bromodeoxyuridine (BrdUrd), a thymidine analogue and radiation sensitizer, inhibits growth and activity of cyclin A-cdk2 kinase in metastatic C8161 and nonmetastatic neo 6.3/C8161 human melanoma cells. Inhibition is not due to altered levels of cyclin D or catalytic cdk2 but involves a decrease in cyclin A and proliferating cell nuclear antigen, paralleled by higher levels of p21WAF1 without increases in p53. In contrast to serum starvation, which prevents accumulation of cyclins A and D in normal fibroblasts, such treatment did not down-regulate either cyclin in these melanoma cells, implying an aberrant control for G1 cyclins in these tumor cells. However, cyclin A was decreased by BrdUrd, suggesting that this pyrimidine analogue arrests melanoma cells at a G1 transition point, unlike that of serum starvation. This is the first report indicating that the antitumor therapeutic action of BrdUrd may be mediated by a p53-independent reciprocal effect on activators and inhibitors of cdk kinases.
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PMID:p53-independent increase in p21WAF1 and reciprocal down-regulation of cyclin A and proliferating cell nuclear antigen in bromodeoxyuridine-mediated growth arrest of human melanoma cells. 882 3


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