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)

Proteases are known to be involved in the apoptotic pathway. We report here that benzyloxycarbonyl (Z)-Leu-Leu-leucinal(ZLLLal), a leupeptin analogue, can induce apoptosis in MOLT-4 and L5178Y cells. ZLLLal is a cell-permeant inhibitor of proteasome. Among the protease inhibitors tested, only calpain inhibitor I (acetyl-Leu-Leu-norleucinal) and ZLLLal caused a marked induction of apoptosis in MOLT-4 cells. In contrast Z-Leu-leucinal, a specific inhibitor of calpain, did not induce apoptosis. When MOLT-4 cells were incubated in the presence of ZLLLal, p53 accumulated in the cells. These results strongly suggest that inhibition of proteasome induces p53-dependent apoptosis and that proteasome can protect cell from apoptosis.
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PMID:Apoptosis induction resulting from proteasome inhibition. 871 62

Heat-induced apoptosis was studied in M10 and MOLT-4 cells by determining nuclear morphological changes, decrease in cell size, DNA degradation into fragments of about 30 kbp, and the appearance of internucleosomal DNA fragments (DNA ladders). Morphological changes in the nucleus were detected within 30 min after heat-treatment at 44 degrees C in M10 cells, but much later (> 5 h) in MOLT-4 cells. In M10 cells, 30 kbp-DNA fragments were observed even at the end of the heat-treatment and decreased 10 min later, while the DNA ladder increased at 10-30 min after heat treatment. DNA fragments of 30 kbp appeared in MOLT-4 cells at 1 h after the heat-treatment and apparently accumulated for up to 24 h. Heat-treatment increased p53 protein in MOLT-4 cells but not in M10 cells. Analysis of the DNA sequence of the p53 gene revealed that M10 cells have a heterozygous mutation in codon 173 of exon 5. These results suggest that apoptosis is induced by hyperthermia in a cell-line dependent manner, that the formation of 30 kbp-DNA fragments is a very early event in apoptosis, that DNA fragmentation into a DNA ladder occurs via the 30 kbp fragments, and that apoptosis in heat-treated M10 cells may be independent of p53.
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PMID:Heat-induced apoptosis and p53 in cultured mammalian cells. 919 97

We surveyed five human hematopoietic cell lines (HSB-2, MOLT-4, Reh, CEM, and HL-60) to determine whether any simple correlates with sensitivity to killing by gamma-irradiation might be revealed. The clonogenic survival gamma-ray dose-response curves for these cell lines cover a wide range of sensitivities. Consistent with previous results for murine hematopoietic cell lines, there was a clear correlation between the rapidity with which irradiation induced apoptosis and clonogenic radiosensitivity of a cell line, although the relationship between timing of apoptosis and radiosensitivity differed between human and murine cell lines. Flow cytometric determination of cell cycle distribution after irradiation showed that differences between human hematopoietic cell lines, in the rate of induction of apoptosis, were generally related to the functioning of cell cycle checkpoints. Whereas the rapidly dying and radiosensitive HSB-2 cell line underwent apoptosis from different points in the cell cycle, the more slowly dying cell lines showed a variety of cell cycle arrest profiles and initiated apoptosis after accumulation of cells in the G2 phase. The lag-phase between arrest in G2 and induction of apoptosis was comparable for MOLT-4, Reh, and CEM; however, HL-60 cells showed a markedly longer G2 arrest that correlated with their greater radioresistance. The results suggest that the total length of time available for DNA damage repair (irrespective of whether this time accrues as blockage in G1, S, or G2), prior to potential activation of apoptosis, is a critical determinant of radiosensitivity in human hematopoietic cell lines. Comparison of the p53 status of these cell lines suggested that mutations in the TP53 gene are contributing to the delay of induction of apoptosis seen in the more radioresistant cell lines. The sensitivity of MOLT-4 and HL-60 cells to killing by DNA-associated 125I decays was determined and was found to correlate with the relative sensitivity of these lines to gamma-irradiation. The highly localized deposition of energy by 125I decays argues that DNA damage is a potent initiator of apoptosis in these cell lines. The results presented suggest that differences in the radiosensitivity of the cell lines examined reflect differences in the rapidity of induction of apoptosis and that radiation-induced cell death in hematopoietic cells can be explained as a response to DNA damage.
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PMID:Explaining differences in sensitivity to killing by ionizing radiation between human lymphoid cell lines. 966 96

DNA damage in the cell activates expression of the p53 tumor suppressor gene, whose role is associated with cell arrest in G1 or apoptosis. The aim of this study was to examine the cell cycle position-related changes in expression of p53, as well as induction of apoptosis, in mitogen-stimulated normal human lymphocytes and in human leukemic MOLT-4 cells (which express mutated p53), following DNA damage by the alkylating agent nitrogen mustard. Measurement of p53 expression and DNA content by flow cytometry followed by bivariate analysis of the data made it possible to correlate the drug-induced changes in p53 expression in individual cells with their cell cycle position without the need for cell synchronization. Expression of p53 was detected immunocytochemically using the AB-6 mAb, which reacts with the product of the wild-type p53 tumor suppressor gene and with most of its mutated forms. Exposure of normal lymphocytes to 5 microM nitrogen mustard caused their arrest in G1, an increase in p53 expression which was maximal in such cells, and significant apoptosis in cells located beyond the arrest point (S and G2 + M cells). In contrast, neither arrest in G1 nor significant apoptosis of MOLT-4 cells was seen after administration of either 0.5 or 5 microM nitrogen mustard for up to 24 h, although the drug reduced the rate of cell progression in the S-phase at both concentrations. Expression of p53 was highest for S and G2 + M MOLT-4 cells in response to the nitrogen mustard. Although a severalfold lower level of p53 was detected in lymphocytes compared to MOLT-4 cells prior to drug treatment, the relative increase in p53 expression in response to the drug was 2-fold higher in lymphocytes. These data suggest that DNA damage caused by nitrogen mustard provides a signal that results in stabilization of wild-type p53, preferentially in G1 cells, causes cell arrest in G1, and induces apoptosis of the cells that either were in the S-phase at the time of drug administration and/or escaped G1 arrest. The increase in expression of mutated p53, in response to DNA damage, is unrelated to the cell cycle position, and neither provides a signal for cell arrest in G1 nor a trigger for immediate apoptosis.
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PMID:Induction of apoptosis and cell cycle-specific change in expression of p53 in normal lymphocytes and MOLT-4 leukemic cells by nitrogen mustard. 981 57

Isohomohalichondrin B (IHB), a novel marine compound with anti-tumoral activity, extracted from the Lissodendorix sponge, inhibits GTP binding to tubulin, preventing microtubule assembly. Cell cycle perturbations and apoptosis induced by IHB were investigated on selected human cancer cell lines by using flow cytometric and biochemical techniques. Monoparameter flow cytometric analysis showed that 1 h IHB exposure caused a delayed progression through S-phase, a dramatic block in G2M phase of the cell cycle and the appearance of tetraploid cell population in LoVo, LoVo/DX, MOLT-4 and K562 cells. At 24 h after IHB exposure, the majority of cells blocked in G2M were in prophase as assessed by morphological analysis and by the fact that they expressed high levels of cyclin A/cdc2 and cyclin B1/cdc2. At 48 h, all cells were tetraploid as assessed by biparameter cyclin A/DNA and cyclin B1/DNA content analysis. Apoptotic death was detected in both leukaemic MOLT-4 and K562 cells, which express wild-type and mutated p53 respectively, when the cells were blocked in mitotic prophase. In conclusion, IHB is a novel potent anti-tumour drug that causes delayed S-phase progression, mitotic block, tetraploidy and apoptosis in cancer cell lines.
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PMID:Cell cycle perturbations and apoptosis induced by isohomohalichondrin B (IHB), a natural marine compound. 988 68

MOLT-4 cells undergo apoptosis after X irradiation. A radiosensitive variant, MOLT-4N1, and a radioresistant variant, MOLT-4N2, have been studied with respect to their radiosensitivity and its relationship to the levels of TP53 protein (formerly known as p53). X irradiation induces apoptosis in both cell lines with the following difference: The induction of apoptosis in MOLT-4N2 cells occurred later than in MOLT-4N1 cells as determined by the morphological changes and DNA fragmentation. The levels of cell death measured by the dye exclusion test coincided with the levels of apoptosis in both cell lines, suggesting that radiation-induced cell killing is determined by the induction of apoptosis. Unirradiated MOLT-4N1 cells contained a significantly higher intracellular level of TP53 protein and a much higher level of TP53 mRNA compared to MOLT-4N2 cells. X irradiation led to an accumulation of TP53 protein in both cell lines that was greater in MOLT-4N1 cells. This accumulation of TP53 protein preceded changes in DNA degradation and ladder formation and in nuclear morphology. These results strongly suggest that the radiosensitivity of MOLT-4 cells correlates well with the unirradiated control levels of TP53 mRNA and TP53 protein, and that the quantitative levels of TP53 protein must reach a threshold for the cells to undergo apoptosis.
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PMID:Correlation between unirradiated cell TP53 protein levels and radiosensitivity in MOLT-4 cells. 1036 Jul 88

Programmed cell death (apoptosis), a form of cell death, described by Kerr and Wyllie some 20 years ago, has generated considerable interest in recent years. The mechanisms by which this mode of cell death (seen both in animal and plant cells), takes place have been examined in detail. Extracellular signals and intracellular events have been elaborated. Of interest to the clinician, is the concentrated effort to study pharmacological modulation of programmed cell death. The attempt to influence the natural phenomenon of programmed cell death stems from the fact that it is reduced (like in cancer) or increased (like in neurodegenerative diseases) in several clinical situations. Thus, chemicals that can modify programmed cell death are likely to be potentially useful drugs. From foxglove, which gave digitalis to the Pacific Yew from which came taxol, plants have been a source of research material for useful drugs. Recently, a variety of plant extracts have been investigated for their ability to influence the apoptotic process. This article discusses some of the interesting data. The ability of plants to influence programmed cell death in cancerous cells in an attempt to arrest their proliferation has been the topic of much research. Various cell-lines like HL60, human hepatocellular carcinoma cell line (KIM-1), a cholangiocarcinoma cell-line (KMC-1), B-cell hybridomas, U937 a monocytic cell-line, HeLa cells, human lymphoid leukemia (MOLT-4B) cells and K562 cells have been studied. The agents found to induce programmed cell death (measured either morphologically or flow cytometrically) included extracts of plants like mistletoe and Semicarpus anacardium. Isolated compounds like bryonolic acid (from Trichosanthes kirilowii var. Japonica, crocin (from saffron) and allicin (from Allium sativum) have also been found to induce programmed cell death and therefore arrest proliferation. Even Chinese herbal medicine "Sho-saiko-to" induces programmed cell death in selected cancerous cell lines. Of considerable interest is the finding that Panax ginseng prevents irradiation-induced programmed cell death in hair follicles, suggesting important therapeutic implications. Nutraceuticals (dietary plants) like soya bean, garlic, ginger, green tea, etc. which have been suggested, in epidemiological studies, to reduce the incidence of cancer may do so by inducing programmed cell death. Soy bean extracts have been shown to prevent development of diseases like polycystic kidneys, while Artemisia asiatica attenuates cerulein-induced pancreatitis in rats. Interestingly enough, a number of food items as well as herbal medicines have been reported to produce toxic effects by inducing programmed cell death. For example, programmed cell death in isolated rat hepatocytes has been implicated in the hepatitis induced by a herbal medicine containing diterpinoids from germander. Other studies suggest that rapid progression of the betel- and tobacco-related oral squamous cell carcinomas may be associated with a simultaneous involvement of p53 and c-myc leading to inhibition of programmed cell death. Several mechanisms have been identified to underlie the modulation of programmed cell death by plants including endonuclease activation, induction of p53, activation of caspase 3 protease via a Bcl-2-insensitive pathway, potentiate free-radical formation and accumulation of sphinganine. Programmed cell death is a highly conserved mechanism of self-defense, also found to occur in plants. Hence, it is natural to assume that chemicals must exist in them to regulate programmed cell death in them. Thus, plants are likely to prove to be important sources of agents that will modulate programmed cell death.
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PMID:Modulation of programmed cell death by medicinal plants. 1072 85

Cells respond to genotoxic stress by activation of many genes, including the tumor suppressor p53. p53 activates transcriptionally target genes, such as p21waf1 and gadd45, which can lead to cell cycle arrest, or bax, which can lead to cell death. We examined the response to genotoxic stress in two hematopoietic cell lines that harbor either wild-type (MOLT-4) or a mutant p53 with a codon 161 mutation (U266). We adapted a multiprobe RNase protection assay (RPA) to determine the steady-state RNA levels, and in combination with nuclear runoff assays, transcriptional rates of multiple stress-induced genes. We found a differential activation of growth arrest and cell death-specific p53 target genes in cells with wild-type or mutant p53. Our results show that genotoxic stress can activate the p21waf1 and gadd45 genes in both cell lines. However, the bax gene was not induced in U266 cells. Bax and gadd45 gene induction could be efficiently blocked by pretreating the cells with the antioxidant compound pyrrolidine dithiocarbamate, suggesting that oxidative stress was involved in these responses. Induction of all three genes in MOLT-4 cells was clearly at the transcriptional level, because we detected transcriptional activity by nuclear runoff RPA assays, and transfection with a consensus p53 binding sequence. U266 cells did not activate the same reporter, in spite of the upregulation of p21waf1 and gadd45 RNA levels. However, the p21waf1-reporter constructs containing 0.9 to 2.4 kb of the native p21 promoter were potently activated in U266 cells. These results indicate a differential regulation of p53 target genes in cells containing wild-type or codon 161 mutant p53.
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PMID:Differential upregulation of p53-responsive genes by genotoxic stress in hematopoietic cells containing wild-type and mutant p53. 1079 22

We found that SAPK/JNK was phosphorylated during X-ray-induced rapid cell death of MOLT-4 cells and that acid Sphingomyelinase inhibitor D609 suppressed the rapid cell death as well as phosphorylation of SAPK/JNK. Also C2-ceramide caused phosphorylation of SAPK/JNK, followed by rapid cell death. Further we isolated X-ray-resistant radiation-hybrid clones from MOLT-4 and 50 Gy irradiated mouse FM3A cells by repeated selections with 3 Gy irradiation. One of them named Rh-1a was found resistant to X-ray- as well as C2-ceramide-induced rapid cell death. Rh-1a cells had mouse DNA but no increase in either mouse or human Bcl-2 determined by Western blotting. Accumulation of p53 after X-irradiation was similarly observed in both parental MOLT-4 and Rh-1a cells. However, contrasting to prolonged and prominent phosphorylated status of SAPK/JNK in MOLT-4 cells, Rh-1a cells exhibited short transient increase and FM3A cells showed no increase of phosphorylated status SAPK/JNK after X-irradiation. Therefore, SAPK/JNK activation is considered important in X-ray-induced rapid cell death or apoptosis of MOLT-4 cells.
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PMID:Involvement of SAPK/JNK pathway in X-ray-induced rapid cell death of human T-cell leukemia cell line MOLT-4. 1082 28

Calpain is a calcium-dependent cysteine protease that is implicated in calcium-dependent cell death, and calpain inhibitors are generally considered as inhibitors of apoptosis. To the contrary, in the present study, we found that calpain inhibitor II (CPI-2) triggers rapid apoptosis in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) cells. All target cell lines were killed by CPI-2, including: ALL-1, a multidrug-resistant BCR-ABL fusion transcript-positive t(9;22) pro-B ALL cell line; RS4;11, a highly radiation-resistant MLL-AF4 fusion transcript-positive t(4;11) pre-pre B ALL cell line; RAMOS, a highly radiation-resistant and p53-deficient Burkitt's lymphoma cell line; DAUDI, a Burkitt's leukemia/lymphoma cell line; NALM-6, a pre-B ALL cell line; and JURKAT and MOLT-3, two T-lineage ALL/NHL cell lines. CPI-2-induced apoptosis in LYN-deficient and BTK-deficient subclones of the DT-40 lymphoma B cell line as effectively as it did in wild-type DT-40 cells. Thus, CPI-2-induced apoptosis is not dependent on the protein tyrosine kinases LYN or BTK. Notably, caspase inhibitor I effectively inhibited CPI-2-induced apoptosis, suggesting that the inhibition of a CPI-2-susceptible protease results in caspase activation, leading to apoptosis in ALL/NHL cells. Unlike the high calpain-expressing ALL/NHL cell lines, myeloid leukemia cell lines HL-60/AML, K562/CML, and U937/AMML, or solid tumor cell lines BT-20/breast cancer, PC-3/prostate cancer, U373/glioblastoma, and HeLa/epitheloid cancer, were not susceptible to the cytotoxicity of CPI-2. Taken together, our results identify calpain as a new molecular target for the treatment of ALL and NHL. CPI-2 and its analogues represent a promising new class of antileukemia/lymphoma agents that deserves further development.
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PMID:Calpain inhibitor II induces caspase-dependent apoptosis in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells as well as some solid tumor cells. 1087 99


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