Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have implicated nucleotides in diverse and unexpected functions related to p53 levels, p53-dependent G0/G1 cell cycle arrest, and the role of dATP in the activation of the caspase-induced apoptosis. Using deoxyadenosine-resistant L1210 cells (ED2 and Y8) that had ribonucleotide reductase that was not sensitive to inhibition by dATP and also exhibited other metabolic alterations, the properties of these cells with respect to the role(s) of nucleotides in these functions were explored. In the ED2 and Y8 cells that did not express p53 protein, the pools of UTP, CTP, ATP, and GTP were markedly decreased. The decreased cellular levels of UTP and CTP did not result in these cells being more sensitive to either PALA or acivicin. The ED2 and Y8 cells did not block in G0/G1 in response to PALA treatment even though the basal cellular concentrations of UTP and CTP were reduced 50 to 80%. While it has been shown that dATP in combination with cytochrome c is involved in the apoptotic pathway, the concentration of exogenous deoxyadenosine required to induce apoptosis in the parental L1210 cells was far in excess of the concentration required to inhibit cell growth. Deoxyadenosine did not cause an increase in apoptosis in the deoxyadenosine-resistant Y8 cells. These data suggest that the new roles ascribed to nucleotides may be specific for the particular cell type under very specific conditions.
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PMID:Cellular responses in mouse leukemia L1210 cells made resistant to deoxyadenosine. 973 Nov 98

Wild-type (WT) mouse leukemia L1210 cells express steady-state levels of the mRNA and protein for p53. However, the p53 expressed by the wild-type cells is a mutant form of p53. A deoxyadenosine-resistant L1210 cell line (Y8) derived from the parental WT L1210 cells does not maintain constitutive levels of p53 mRNA or protein. Upon DNA damage, induced by doxorubicin, neither the WT nor the Y8 cells block in G0/G1; the cells block in G2/M. However, treatment of the Y8 cells with doxorubicin results in a much greater fraction of cells becoming apoptotic compared to the WT cells. Doxorubicin treatment resulted in the induction of p53 mRNA in the WT cells, but not the Y8 cells. WAF1, c-myc and Bax mRNAs were also induced by doxorubicin in the WT cells but not in the Y8 cells. The constitutive levels of WAF1 and Gadd45, unexpectedly seen in the p53-deficient Y8 cells, decreased following doxorubicin treatment. The comparison of the effects of DNA damage, as measured by mRNA levels, induced by X-irradiation or doxorubicin were found to vary between the WT and Y8 cells and for the particular mRNA studied. The effect of doxorubicin or X-irradiation on the cell cycle could be overridden in the WT cells by caffeine. Comparisons of DNA damage induced by doxorubicin or X-irradiation show that although the Y8 cells are more sensitive to these damaging agents than the WT cells, the effects on gene expressions are not identical.
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PMID:Effect of doxorubicin on wild-type and deoxyadenosine-resistant mouse leukemia L1210 cells. 1020 Mar 38

Wild-type (WT) mouse leukemia L1210 cells express steady-state levels of p53 mRNA and protein. However, the p53 expressed by the wild-type L1210 cells was found to be a mutant form of p53 (relative to normal mouse fibroblast p53 sequence) having a point mutation in the DNA binding domain of p53. A deoxyadenosine-resistant L1210 cell line (Y8) derived from the parental WT cells had previously been shown to lack the expression of p53 but to respond to cycloheximide (CHX) treatment by superinduction of p53 mRNA. The mRNA for p53 induced by CHX had the same sequence as the p53 from normal mouse fibroblasts. Although the Y8 cells had no constitutive levels of p53 mRNA or protein, the Y8 cells expressed constitutive levels of WAF1 mRNA and protein. Gadd45 mRNA was also present in the Y8 cells. Subjecting the WT or Y8 cells to ionizing radiation did not result in a G0/G1 cell cycle block; the cells blocked in G2/M. The Y8 cells were much more sensitive to the irradiation treatment than the WT cells, resulting in marked increases in apoptosis in the Y8 cells. Although radiation treatment induced p53 mRNA, but no p53 protein, in the Y8 cells, WAF1 mRNA was induced in the Y8 cells. These data indicate that there are p53-independent pathway(s) that may still involve WAF1 and Gadd45 with respect to cell cycle control and apoptosis.
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PMID:Effect of ionizing radiation on wild-type and mutant mouse leukemia L1210 cells. 1022 21

An L1210 cell line selected for resistance to deoxyadenosine (Y8) has been shown to have barely detectable levels of p53 mRNA and no measurable p53 protein in comparison to the parental mouse wild-type (WT) L1210 cells. We now show that the protein synthesis inhibitors, anisomycin and cycloheximide, arrest WT cells in the G1 phase of the cell cycle and induce apoptosis in Y8 cells via a p53-independent mechanism. There was a decrease in Rb phosphorylation but without the induction of WAF1 protein. Anisomycin treatment activated NF kappa B in the WT cells as early as 0.5 hr after treatment but did not activate NF kappa B in the Y8 cells. Cycloheximide was neither as potent as anisomycin in arresting WT cells at G1 and inducing apoptosis in Y8 cells, nor as potent in decreasing Rb phosphorylation. The finding that caffeine could override the G1 arrest induced by anisomycin and cycloheximide in the WT cells further supports the idea that the effects of anisomycin or cycloheximide on the cell cycle are at the level of cell cycle regulation, and are likely not mediated exclusively through the inhibition of protein synthesis.
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PMID:p53-independent anisomycin induced G1 arrest and apoptosis in L1210 cell lines. 1022 77

The deoxyadenosine-resistant mouse leukemia L1210 cell line (Y8) has previously been shown to have phenotypic differences that appear unrelated to the altered properties observed at the level of ribonucleotide reductase (RR). In response to various stress factors, the parental wild-type (WT) L1210 cell line undergoes cell cycle arrest; Y8 cells become apoptotic. These responses are p53-independent. Cell cycle regulation also appears different between the two cell lines, suggesting that Y8 cells are more apoptotic because of alterations in their cell cycle compared to WT cells. In order to study the relationships between cell cycle regulation and apoptosis, the effects of 2-aminopurine (2-AP), wortmannin, and PD98059, were studied on WT and Y8 cells. 2-AP induced G2/M block in both WT and Y8 cells with differences in G0/G1 and S phase contents between the two cell lines. Wortmannin induced G0/G1 block in Y8 cells, while exhibiting no effect on WT cells. PD98059 had no effect on the cell cycle of either WT or Y8 cells. In response to each inhibitor, Y8 cells underwent apoptosis to a much greater extent than the parental WT cell line. These data suggest that the specific pathways that converge on the cell cycle are altered and may be involved in the differences between a tumor cell to block in cell cycle or to undergo apoptosis.
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PMID:Altered sensitivity of deoxyadenosine-resistant mouse leukemia L1210 cells to various kinase inhibitors. 1036 49

The deoxyadenosine-resistant mouse leukemia L1210 cell line (Y8) has previously been shown to be more sensitive to apoptosis induced by DNA damaging agents and by protein synthesis inhibitors than the parental wild-type L1210 (WT) cells. These responses occur independently of p53 as both cell lines lack wild-type p53 function. Recent evidence suggests that a serine/threonine kinase is involved in the divergent cellular responses of the WT and Y8 cells. In the present study, the effects of 7-hydroxystaurosporine (UCN-01), a relatively specific serine/threonine kinase inhibitor, were examined in the WT and Y8 cells. Both cell lines were equally sensitive to the growth inhibitory effects of UCN-01. However, the Y8 cells accumulated in G0/G1 and became apoptotic. Apoptosis induced by UCN-01 in the Y8 cells was mediated by a caspase-3-like activity which could be partially blocked by Ac-DEVD-CHO, a caspase-3 inhibitor. UCN-01 did not alter the phosphorylation status of cdc2 nor cyclin B1 and cdc2 protein levels in either cell line.
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PMID:Altered sensitivity of deoxyadenosine-resistant mouse leukemia L1210 cells to apoptosis induced by 7-hydroxystaurosporine. 1099 94

The deoxyadenosine-resistant mouse leukemia L1210 cell line (Y8) has previously been shown to have phenotypic differences that appear to be unrelated to the altered properties observed at the level of ribonucleotide reductase (RR). One of these changes is that the Y8 cells do not express p53. In response to DNA damaging agents, x-irradiation and doxorubicin, both the parental wild-type L1210 (WT) and Y8 cells undergo G2/M arrest, which is consistent with cells lacking wild-type p53 function. However, Y8 cells are much more sensitive to apoptosis induced by these agents than WT cells. Previous studies have also shown that expression of certain genes involved in cell cycle regulation is different between WT and Y8 cells. Recent evidence suggests that a serine/threonine kinase is involved in the divergent cellular responses of these cells. In the present study, the effects of roscovitine, a cyclin-dependent kinase inhibitor, were examined on the WT and Y8 cells. The WT cells blocked in G2/M, whereas Y8 cells became apoptotic. Apoptosis induced by roscovitine in the Y8 cells was mediated by a caspase-3-like activity. NF kappa B was activated to a much greater extent by roscovitine in the WT cells than in Y8 cells. The data also indicate that cyclin B1/cdc2 plays a role in the divergent p53-independent G2/M block and apoptotic responses of the WT and Y8 cells, respectively. Several key factors such as cathepsin B, caspase-1, release of cytochrome c into the cytosol, TNF-alpha signaling, FasL/Fas signaling, c-myc overexpression, and E2F-1 overexpression and induction were shown not to be involved in the apoptotic pathway(s) in the Y8 cells.
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PMID:Enhanced roscovitine-induced apoptosis is mediated by a caspase-3-like activity in deoxyadenosine-resistant mouse leukemia L1210 cells. 1113 34

Mouse leukemia L1210 cells selected for resistance to deoxyadenosine contain ribonucleotide reductase that is not feedback inhibited by dATP. These deoxyadenosine-resistant cells (Y8) also do not express p53 protein but do have WAF1 and Gadd45 mRNA and protein. The Y8 cells show increased sensitivity to DNA damaging agents and kinase inhibitors. In these studies we show that in the presence of sodium salicylate (NaSal), the parental wild-type (WT) cells block in G2/M phase of the cell cycle while the Y8 cells show a marked increased in the G0/G1 population of cells. The Y8 cells are more sensitive to apoptosis induced by NaSal than the WT cells. NaSal treatment causes the induction of caspase-3-like activity in Y8 cells but no induction of caspase-3 activity in the WT cells. The caspase inhibitor, Ac-DEVD-CHO, decreased the percentage of Y8 cells in the early apoptotic fraction, but this decrease was reflected by an increase in the percent of cells in the late apoptotic/necrotic fraction. SB20358, a p38-MAP kinase inhibitor did not protect the Y8 cells from NaSal-induced apoptosis indicating that the p38-MAP kinase pathway was not involved in the NaSal-induced apoptotic pathway in the p53-independent Y8 cells.
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PMID:Increased sensitivity to sodium salicylate-induced apoptosis in drug-resistant leukemia L1210 cells. 1129 31

A mouse leukemia L1210 cell line (Y8) selected for resistance to deoxyadenosine was found to be deficient in the expression of p53 mRNA and protein while maintaining the expression of WAF1/p21 mRNA and protein even under basal conditions. The Y8 cells were shown to be more sensitive to apoptosis induced by a variety of agents when compared to the parental wild-type (WT) L1210 cells. Roscovitine, an inhibitor of cdk 2 and cdk5, was one of the agents that caused increased apoptosis in the Y8 cells through a pathway that ultimately involved the activation of caspase-3 activity. In these studies, the effects of leflunomide and parthenolide (drugs reported to alter the activation of NFkappaB in a variety of cell types) were studied for their cell cycle and apoptotic effects in WT and Y8 cells as single agents and in combination with roscovitine. Leflunomide at IC50 concentrations had little effect on the cell cycle distribution of either the WT or Y8 cells while at higher concentrations caused a G0/G1 block in Y8 cells. Parthenolide, at IC50 concentrations, caused a G0/G1 cell cycle block in the WT and Y8 cells but at higher concentrations caused a G2/M block in the Y8 cells. The combinations of leflunomide and roscovitine or parthenolide and roscovitine did not alter, in a significant way the cell cycle distribution of the Y8 cells. However, in the presence of the combinations of leflunomide and roscovitine or parthenolide and roscovitine there were large increases in the fraction of Y8 cells undergoing early apoptosis without a corresponding increase in the necrotic fraction of cells. These data show that combinations of agents directed at different pathways or different steps of pathways involved in apoptosis can cause the cells to reach an apoptotic threshold that results in synergistic apoptosis.
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PMID:Augmentation of apoptosis responses in p53-deficient L1210 cells by compounds directed at blocking NFkappaB activation. 1191 Dec 51

An L1210 cell line (Y8) selected for resistance to deoxyadenosine does not express p53 mRNA or protein but expresses WAF1/p21 even under basal conditions. The Y8 cell line had been previously shown to have an increased apoptotic response to a variety of agents that included DNA damaging agents, kinase inhibitors and drugs directed at NFkappa B activation. In this study we show that lactacystin (LC, an inhibitor of proteasome activity) in combination with parthenolide (PA) caused a synergistic increase in the apoptotic fraction of the Y8 cells. LC (2.5 microM) alone and PA (5.0 microM) caused less than 20% of the Y8 cells to undergo apoptosis. However, the combination of LC (2.5 microM) plus PA (5.0 microM) caused 60% of the Y8 cells to undergo apoptosis. The combination of drugs had no effects on the parental wild-type L1210 cells. Pretreatment of the intact Y8 cells with the caspase-3 inhibitor, Ac-DEVD-CHO, resulted in a marked decrease in the apoptosis caused by the LC plus PA combination. Cell-free extracts prepared from the LC plus PA combination-treated cells had activated caspase activities in the caspase cascade: caspase-3 >> caspase-8 > caspase-6 and caspase-10. These results suggest that there are interacting pathways involving aspects of NFkappa B activation and proteasome activity that could be exploited in therapy directed at p53-deficient tumor cells that would lead to caspase-3 activation and apoptosis bypassing the p53-dependent chemotherapy insensitivity.
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PMID:Lactacystin, a proteasome inhibitor, potentiates the apoptotic effect of parthenolide, an inhibitor of NFkappaB activation, on drug-resistant mouse leukemia L1210 cells. 1255 98


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