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)

Immunostaining demonstrated that p53 protein was localized in the cytoplasm of growing MCF-7 cells and in the nuclei of cells that were growth arrested by serum starvation. Serum stimulation of the arrested cells induced marked increases in DNA synthesis and p53 phosphorylation, and translocation of the protein from the nucleus to the cytoplasm at 20 h after the stimulation. This increase in the DNA synthesis that was significantly inhibited by TGF-beta 1 was coincident with the inhibition of phosphorylation and cytoplasmic translocation of the p53 protein.
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PMID:Inhibition of DNA synthesis by TGF-beta 1 coincides with inhibition of phosphorylation and cytoplasmic translocation of p53 protein. 156 96

To further characterize the role of p53 in growing normal Balb/c 3T3 fibroblasts, as well as of p53 in cells of the methylcholanthrene induced fibrosarcoma cell line Meth A, we analysed the effect of inhibition of p53 synthesis by microinjection of p53-specific monoclonal antibody PAb 122 into the nuclei of these cells after release from growth arrest induced by isoleucine starvation (see preceding paper [Steinmeyer et al., this issue] ). We show that microinjection of PAb 122, but not of control immunoglobulins, into the nuclei of both types of cells effectively blocked their re-entry into the S-phase of the cell cycle. Since isoleucine depletion of these cells was shown to lead to a growth arrest at the restriction point (R-point) in the G1-phase of the cell cycle, our results (i) define more precisely the role of p53 in growing cells as a protein controlling transition of the cells through this restriction point, and (ii) demonstrate that mutated p53 in Meth A cells still is functional with regard to cell cycle control at this restriction point. We suggest that p53 acts as a 'gate-keeping' protein at restriction points in the cell cycle, exerting a positive effect on the transition of cells through the cell cycle.
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PMID:Cell cycle control of p53 in normal (3T3) and chemically transformed (Meth A) mouse cells. II. Requirement for cell cycle progression. 226 36

Expression of the oncogenes c-myc, c-raski, and p53 is studied in normal primary mouse cultures and in two adenovirus-transformed mouse cell lines. In all cases oncogene expression is measured in cells arrested in G1 (or G0 for primary cells) by serum starvation and at different times after cell cycle traverse is stimulated by addition of high serum. For primary mouse cells, c-myc mRNA levels are found to increase four- to six-fold within 1 h of serum addition and then decline by 4 h to nearly the level observed in serum-starved cells. This level is maintained throughout the remainder of the cell cycle. The early induction of c-myc is dependent on serum concentration and is independent of cell density. These results confirm and extend previous observations for primary cells. By contrast, expression of c-raski does not vary at all through the cell cycle and p53 increases with time after mitogenic stimulation. In the adenovirus-transformed cell lines, the regulation of expression of c-myc with respect to the cell cycle is altered. There is an increase in c-myc in S phase cells which is dependent on cell density and the early induction in response to serum addition as seen in primary cells is absent. Expressions of c-raski and p53 are found to show similar profiles to those observed for primary cells.
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PMID:Altered regulation of c-myc expression in adenovirus-transformed cells. 380 68

To better understand how the E2F1 transcription factor contributes to the process of cell proliferation, NIH-3T3 cell lines were generated that constitutively express either the wild-type E2F1 protein or an amino terminal deletion mutant, termed E2F1d87. Proliferating E2F1d87-expressing cells exhibit a significant lengthening of S phase relative to control and E2F1 cell lines and are hypersensitive to the cytotoxic effects of the S phase-specific antitumor drug camptothecin. This sensitivity is associated with an increase in drug-induced p53 and WAF1 levels. The E2F1 and E2F1d87 cell lines are both able to initiate, but not complete, S phase under conditions of serum starvation. However, quantitation of DNA synthesis, during culture in serum-deprived media, indicates that the E2F1d87 cell line synthesizes more DNA/cell as compared to the E2F1 cell line. Consistent with this relative increase in DNA synthesis, the E2F1d87 cell line undergoes camptothecin-induced apoptosis when cultured under conditions of serum starvation, while the control and E2F1 cell lines are unaffected by drug treatment under the same conditions. Thus, the sensitivity of the E2F1d87 cell line to camptothecin is not dependent on cell proliferation. The data presented here suggest that cell cycle parameters can be manipulated in order to enhance sensitivity of a cell to the toxic effects of specific chemotherapeutic agents.
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PMID:Expression of a deletion mutant of the E2F1 transcription factor in fibroblasts lengthens S phase and increases sensitivity to S phase-specific toxins. 754 Sep 51

When deprived of autocrine growth factors, Epstein-Barr virus (EBV)-immortalized B cells stop growing and die. In this study, we show that death of EBV-immortalized cells deprived of autocrine growth factors occurred by apoptosis. Cycloheximide, a protein synthesis inhibitor, inhibited apoptosis, suggesting that de novo protein synthesis is required. Because p53, Bcl-2, and c-Myc were previously implicated in the induction or prevention of apoptosis in other systems, we assessed their possible involvement here. Unlike normal cells that respond to growth factor deprivation by down-regulating c-Myc expression, EBV-immortalized cells continued to express c-Myc, p53, and Bcl-2 at levels comparable to those measured prior to starvation. Consistent with data demonstrating that c-Myc expression is sufficient to drive quiescent cells into the cell cycle, autocrine growth factor-deprived EBV-immortalized cells did not undergo growth arrest but rather continued to proliferate until death, which occurred randomly throughout the cell cycle. In contrast to EBV-immortalized B cells, normal peripheral blood B cells activated in vitro with anti-CD40 monoclonal antibody and interleukin 4 rapidly down-regulated c-Myc expression and underwent growth arrest in response to growth factors and serum deprivation. These findings demonstrated that c-Myc expression is deregulated in EBV-immortalized cells. Addition of antisense oligonucleotides to c-Myc specifically promoted the survival of starved EBV-immortalized cells and suppressed growth of nonstarved EBV-immortalized cells. Thus, deregulated expression of c-Myc in EBV-immortalized cells promotes proliferation and apoptosis following autocrine growth factor deprivation.
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PMID:A role for deregulated c-Myc expression in apoptosis of Epstein-Barr virus-immortalized B cells. 780 56

Apoptotic cell death is an active process which regulates the maintenance of the hematopoietic homeostasis. It has been reported that wild-type p53 (wt-p53) protein induces apoptosis in leukemia cells. To assess whether p53 is involved in the apoptotic process of normal hematopoietic cells, we introduced the temperature-sensitive p53Val135 mutant into the murine myeloid precursor cell line 32Dcl3. These are diploid, non-tumorigenic cells whose survival and proliferation are dependent upon growth factor supply (IL-3 and serum). Overexpression of wt-p53 protein does not affect morphology and proliferation of 32D cells as long as they are maintained in the presence of IL-3. However, after IL-3 withdrawal, wt-p53 overexpression significantly accelerates apoptosis. This phenomenon is IL-3 specific since no differences in death rates induced by serum starvation are found between parental cells and p53-transfectants. When the latter experiments are carried out at 37 degrees C with p53 protein in mutant conformation, an extended survival of 32D cells is observed after IL-3 deprivation, but not after serum withdrawal. Taken together, these results show that wt-p53 actively mediates the apoptosis due to the absence of specific growth factors, such as IL-3, suggesting that p53 might be involved in the response of myeloid precursors to environmental cytokines for the maintenance of the hematopoietic homeostasis.
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PMID:Wild-type p53 modulates apoptosis of normal, IL-3 deprived, hematopoietic cells. 786 50

In normal human fibroblast cells, the primary cell cycle regulators, the cyclin-dependent kinases (CDKs), exist predominantly in multiple quaternary complexes, each consisting of a CDK, a cyclin, proliferating cell nuclear antigen (PCNA) and p21. p21 encodes a universal inhibitor of cyclin-dependent kinases. Here we show that the level of p21 mRNA and the interaction of p21 protein with cyclin-CDK enzymes are regulated during the cell cycle. When normal human fibroblast IMR90 cells were released from serum starvation, p21 mRNA reached its highest level immediately following serum stimulation, began to decrease at the G1/S boundary, fell to its lowest level during S phase, and accumulated again as cells exited from S phase. p21 protein associates with each cyclin-CDK complex in a cell cycle dependent manner. Cyclin A-CDK2-p21-PCNA and Cyclin B1-CDC2-p21-PCNA complexes are assembled in early S and G2 phase, respectively, indicating that p21 and/or PCNA regulates the enzymatic activity of each kinase at the time of their functioning. Cyclin D1-CDK4-p21-PCNA complexes, on the other hand, persist throughout the cell cycle, suggesting that cyclin D1-CDK4 quaternary complexes may play a role in monitoring an event(s) that may occur at any time, rather than at a specific stage of the cell cycle. The level of p21 mRNA in early passage Li-Fraumeni cells that are heterozygous for p53 mutation remained similar to that in normal fibroblasts, but was undetectable in immortalized Li-Fraumeni cells homozygous for mutant p53. This finding provides a plausible molecular explanation for the loss of genetic stability associated with cells homozygous, but not heterozygous, for p53 mutation.
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PMID:Cell cycle expression and p53 regulation of the cyclin-dependent kinase inhibitor p21. 791 44

WAF1/Cip1 was recently identified as the wild-type p53 target that appears to mediate the tumor suppressing effects of p53. We investigated the mechanisms of regulation of WAF1/Cip1 gene expression in human breast carcinoma (HBC) cells. Our results demonstrate that the HBC cells harboring wild-type p53 express 26-33-fold higher WAF1/Cip1 mRNA levels than the cells harboring mutant p53. The DNA damaging agent etoposide induced p53 accumulation only in cells harboring wild-type p53 yet it induced WAF1/Cip1 gene expression in cells carrying wild-type or mutant p53, suggesting the involvement of p53-dependent and independent signaling pathways in the regulation of WAF1/Cip1 gene expression. Serum starvation-induced growth arrest although not altering the endogenous p53 levels or its ability to transactivate the reporter gene, induced WAF1/Cip1 gene expression in cells carrying wild-type as well as mutant p53. These results further implicated the involvement of p53-independent signal transduction pathways in WAF1/Cip1 gene regulation. Our data also suggest that WAF1/Cip1 gene expression is tightly associated with cell cycle progression in cells containing either wild-type or mutant p53. WAF1/Cip1 expression was transiently induced in response to serum treatment and declined as the cells passed through the S-phase of the cell cycle. We thus provide evidence that the mechanisms of WAF1/Cip1 gene regulation involve p53-dependent and independent signaling pathways in HBC.
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PMID:Mechanisms of regulation of WAF1/Cip1 gene expression in human breast carcinoma: role of p53-dependent and independent signal transduction pathways. 797 Jun 99

Deregulated expression of the c-myc proto-oncogene can lead to apoptosis under certain physiological conditions. By introducing a conditionally active Myc allele into primary embryo fibroblasts null for p53, and into fibroblasts without endogenous p53 expression but ectopically expressing a temperature-sensitive p53 allele, we show that expression of wild-type p53 is required for susceptibility to Myc-mediated apoptosis. Although ectopic expression of wild-type p53 blocked cells in the G1 phase of the cell cycle, G1 arrest by isoleucine starvation, in a manner independent of p53, did not confer susceptibility to apoptosis. Thus, growth arrest per se is not sufficient to induce Myc-mediated apoptosis; instead, a property intrinsic to p53 is specifically required. Moreover, apoptosis did not require induction of p53 target proteins, including the cyclin-dependent kinase inhibitor p21waf1/cip1. Therefore, the role of p53 in apoptosis may be distinct from its role in cell cycle arrest.
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PMID:Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1. 799 20

The tumor suppressor p53 can function as a sequence-specific transcription factor and is required for activation by ionizing radiation (IR) of one or more downstream effector genes, such as the human GADD45 gene. One important consequence of IR that is probably mediated by these downstream effector genes is activation of the p53-mediated G1 cell cycle checkpoint. While the induction of reporter constructs containing p53-binding sites has already been demonstrated with p53 expression vectors, we have now demonstrated the direct activation of such a construct after treatment of the human RKO line, which has a normal p53 phenotype, with various types of DNA-damaging agents and also after growth arrest produced by medium depletion (starvation). IR, UV radiation, and methylmethane sulfonate were found to induce p53 activity when a stably integrated reporter construct containing functional p53-binding sites was used and also in mobility shift assays with a p53-binding site from the GADD45 gene, and IR-inducible gene previously associated with growth arrest. The same cell treatments that induced this p53 activity also caused an increase in cellular p53 protein levels. The response in cells lacking normal p53 or in RKO cells expressing a dominant negative mutant p53 was markedly reduced. Interestingly, the spectrum of effective inducing agents for the above-described experiments was similar to that which induces GADD45 either in cells with a normal p53 status or, with the exception of IR, in cells lacking normal p53. These results indicate a role for p53 in the IR pathway, which is completely p53 dependent, and in other genotoxic stress responses, in which p53 has a cooperative effect but is not required.
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PMID:Induction of cellular p53 activity by DNA-damaging agents and growth arrest. 832 Dec 26


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