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)

Ionizing radiation is a major tool for cancer treatment. The response of eukaryotic cells to ionizing radiation includes apoptosis, a process which requires activation of multiple genes. We sought to determine whether radiation-induced gene expression plays a role in radiation-induced apoptosis. We found Apo2 ligand (Apo2L, also called TRAIL) mRNA induction following gamma-irradiation of Jurkat, MOLT-4, CEM, and PBMC, all human T lineage-derived cells. Increased Apo2L protein levels were found in MOLT-4 and Jurkat cells. Radiation also activated the Apo2L death receptor (DR)5 (also called Apo2, TRAIL-R2, or KILLER) in MOLT-4 cells, which harbor a wild-type p53. We isolated 1152 bp of 5' flanking region of the Apo2L gene and a shorter fragment of 716 bp, both of which showed promoter activity driving the expression of a luciferase reporter gene; however, the response to radiation in MOLT-4 cells was lost when only 430 bp of 5' proximal flanking sequence was maintained. Exogenous Apo2L induced phosphatidylserine exposure on cell membranes, caspase 8 and caspase 3 activation, key markers of apoptosis, confirming that the Apo2L/DR5 pathway is functional in these cells. Bid, a Bcl-2 family protein also known to contribute to receptor-mediated apoptosis, was also activated. To determine whether Apo2L and DR5 were critical for radiation signaling to apoptosis, we stably expressed a dominant negative DR5delta-receptor in Jurkat cells. Cell survival was significantly augmented, indicating that increased Apo2L expression contributed to radiation-induced apoptosis. Clonogenic assays demonstrated that purified, recombinant soluble Apo2L enhanced the lethality of low, therapeutic doses (1-2 Gy) of gamma-irradiation. These data suggest that production of Apo2L may cooperate synergistically with the cytotoxic effect of radiation, and that combinations of Apo2L and radiation may become a powerful tool in clinical therapy.
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PMID:Apo2 ligand/TNF-related apoptosis-inducing ligand and death receptor 5 mediate the apoptotic signaling induced by ionizing radiation in leukemic cells. 1105 70

In the present study, we investigated the in vitro apoptotic response of leukemic cells to the cellular stress induced by homoharringtonine (HHT), a plant alkaloid with antileukemic activity which is currently being tested for treatment of acute and chronic leukemias. A comparison of leukemic cell lines with different p53 gene status revealed a considerably higher sensitivity to HHT-induced apoptosis in the cells with a wt p53, and apoptotic events in wt p53 leukemia cells (MOLT-3 cell line) were studied in more detail. To this end, we examined components of apoptotic cascades including Bax expression and its intracellular localization, changes of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) levels, cytochrome c release from mitochondria and activation of caspases. Bax protein levels did not increase despite an up-regulation of bax at mRNA level. However, Bax translocation from cytosol towards mitochondria was observed. In addition, we observed a release of cytochrome c from the mitochondria, and the localization changes of both Bax and cytochrome c were found already at the early, annexin V-negative stage of HHT-induced apoptosis. HHT-treated MOLT-3 cells revealed loss of MMP as well as activation of caspases demonstrated by DEVD-, IETD- and LEHD-tetrapeptide cleavage activity in the cell lysates. ROS levels only slightly increased in HHT-treated cells and antioxidants did not prevent apoptosis and MMP changes. Therefore, wt p53 leukemic cells respond to HHT-specific cellular stress by induction of ROS-independent apoptotic pathway characterized by translocation of Bax, mitochondrial cytochrome c release and activation of caspases.
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PMID:Apoptotic response to homoharringtonine in human wt p53 leukemic cells is independent of reactive oxygen species generation and implicates Bax translocation, mitochondrial cytochrome c release and caspase activation. 1136 58

The effects of varying concentrations of linoleic acid and its transisomer linolelaidic acid on the proliferation the ultrastructural morphology of MOLT-4 T-lymphoblastic leukaemia cells were investigated. At 2 and 4 days after exposure to the fatty acids, the cells were counted by flow cytometry and observed by electron microscopy. After 4 days of treatment, linoleic acid was growth stimulatory at concentrations of 200 microM or less, but was markedly inhibitory at 400 microM. In contrast, linolelaidic acid stimulated proliferation at concentrations of 100 and 200 microM, but inhibited cell growth at 400 microM. Cells treated with 400 microM linoleic acid displayed dense accumulations of characteristic lipid globules and glycogen granules, and exhibited ultrastructural evidence of apoptosis including vacuolization, membrane blebbing and chromatin margination at the nuclear periphery. These results support the notion that geometrical isomerism and concentration of polyunsaturated fatty acids influence the proliferative destiny of cancer cells. Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed a previously documented larger alternatively spliced p53 gene transcript in MOLT-4 cells cultured under reduced serum conditions. However, only wild-type p53 transcripts were amplified by RT-PCR of MOLT-4 cells exposed to phytohaemagglutinin, linoleic acid or linolelaidic acid.
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PMID:Linoleic and linolelaidic acids differentially influence proliferation and apoptosis of MOLT-4 leukaemia cells. 1148 1

There are several pathways leading to apoptosis. It is not clear whether cells choose one of them or use multiple processes when they commit to apoptosis. MOLT-4 cells undergo apoptosis after X-irradiation through the p53-dependent pathway and/or ceramide signal. To evaluate the relative contribution of these pathways, we studied effects of the expression of various levels of transfected murine mutant p53 cDNA (TGC-->CGC of codon 173, corresponding to codonl76 in human p53) on the induction of apoptosis in X-irradiated or heated MOLT-4 cells. When survival was determined by the dye-exclusion test at 24 h after irradiation, the percentage of X-ray- or heat-induced dead cells was markedly decreased, depending on the expression level of mutant p53 protein in transfected clones. The appearance of apoptotic cells as determined by morphological changes was also decreased. These inhibitions were almost complete at 24 h after irradiation with X-rays in the case of the highest-expressing clone. p21 WAF1 protein was increased in MOLT-4 cells after X-irradiation, but not in the transfectant. These results suggest that murine mutant p53 protein has a dominant-negative effect against normal p53 in MOLT-4, and that the X-ray-induced apoptosis in MOLT-4 is fully p53-dependent.
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PMID:Evaluation of the relative contribution of p53-mediated pathway in X-ray-induced apoptosis in human leukemic MOLT-4 cells by transfection with a mutant p53 gene at different expression levels. 1168 71

The nef gene product of human immunodeficiency virus type 1 (HIV-1) is important for the induction of AIDS, and key to its function is its ability to manipulate T-cell function by targeting cellular signal transduction proteins. We reported that Nef coprecipitates a multiprotein complex from cells which contains tumor suppressor protein p53. We now show that Nef interacts directly with p53. Binding assays showed that an N-terminal, 57-residue fragment of Nef (Nef 1-57) contains the p53-binding domain. Nef also interacted with p53 during HIV-1 infection in vitro. As p53 plays a critical role in the regulation of apoptosis, we hypothesized that Nef may alter this process. Nef inhibited UV light-induced, p53-dependent apoptosis in MOLT-4 cells, with Nef 1-57 being as effective as its full-length counterpart. The inhibition by Nef of p53 apoptotic function is most likely due its observed ability to decrease p53 protein half-life and, consequently, p53 DNA binding activity and transcriptional activation. These data show that HIV-1 Nef may augment HIV replication by prolonging the viability of infected cells by blocking p53-mediated apoptosis.
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PMID:Human immunodeficiency virus type 1 Nef binds to tumor suppressor p53 and protects cells against p53-mediated apoptosis. 1186 36

A(3) adenosine receptor (A(3)AR) agonists have been reported to influence cell death and survival. The effects of an A(3)AR agonist, 1-[2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta-D-ribofuranonamide (Cl-IB-MECA), on apoptosis in two human leukemia cell lines, HL-60 and MOLT-4, were investigated. Cl-IB-MECA (> or =30 microM) increased the apoptotic fractions, as determined using fluorescence-activated cell sorting (FACS) analysis, and activated caspase 3 and poly-ADP-ribose-polymerase. Known messengers coupled to A(3)AR (phospholipase C and intracellular calcium) did not seem to play a role in the induction of apoptosis. Neither dantrolene nor BAPTA-AM affected the Cl-IB-MECA-induced apoptosis. Cl-IB-MECA failed to activate phospholipase C in HL-60 cells, while UTP activated it through endogenous P2Y(2) receptors. Induction of apoptosis during a 48hr exposure to Cl-IB-MECA was not prevented by the A(3)AR antagonists [5-propyl-2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] (MRS 1220) or N-[9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5-yl]benzeneacetamide (MRS 1523). Furthermore, higher concentrations of MRS 1220, which would also antagonize A(1) and A(2A) receptors, were ineffective in preventing the apoptosis. Although Cl-IB-MECA has been shown in other systems to cause apoptosis through an A(3)AR-mediated mechanism, in these cells it appeared to be an adenosine receptor-independent effect, which required prolonged incubation. In both HL-60 and MOLT-4 cells, Cl-IB-MECA induced the expression of Fas, a death receptor. This induction of Fas was not dependent upon p53, because p53 is not expressed in an active form in either HL-60 or MOLT-4 cells. Cl-IB-MECA-induced apoptosis in HL-60 cells was augmented by an agonistic Fas antibody, CH-11, and this increase was suppressed by the antagonistic anti-Fas antibody ZB-4. Therefore, Cl-IB-MECA induced apoptosis via a novel, p53-independent up-regulation of Fas.
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PMID:p53-Independent induction of Fas and apoptosis in leukemic cells by an adenosine derivative, Cl-IB-MECA. 1191 39

The retinoid, N-(4-hydroxyphenyl)retinamide (4-HPR), mediates p53-independent cytotoxicity and can increase reactive oxygen species and ceramide in solid tumor cell lines. We determined changes in ceramide and cytotoxicity upon treatment with 4-HPR (3-12 microM) in six human acute lymphoblastic leukemia (ALL) cell lines: T cell (MOLT-3, MOLT-4, CEM), pre-B-cell (NALM-6, SMS-SB), and null cell (NALL-1). Exposure to 4-HPR (12 microM) for 96 h caused 4.7 (MOLT-3), 3.5 (MOLT-4), 3.9 (CEM), 2.9 (NALM-6), 4.7 (SMS-SB), AND 4.5 (NALL-1) logs of cell kill. The average 4-HPR concentration that killed 99% of cells (LC(99)) for all six lines was 4.8 microM (range: 1.5-8.9 microM). Treatment with 4-HPR (9 microM) for 24 h resulted in an 8.9 +/- 1.0-fold (range: 4.9-15.7-fold) increase of ceramide. Ceramide increase was time- and dose-dependent and abrogated by inhibitors of de novo ceramide synthesis. Concurrent inhibition of ceramide glycosylation/acylation by d,l-threo-(1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol) (PPMP) further increased ceramide levels, and synergistically increased 4-HPR cytotoxicity in four of six ALL cell lines. 4-HPR was minimally cytotoxic to peripheral blood mononuclear cells and a lymphoblastoid cell line, and increased ceramide <2-fold. Thus, 4-HPR was cytotoxic and increased ceramide in ALL cell lines, but not in non-malignant lymphoid cell types.
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PMID:N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes. 1198 53

We demonstrated that enhancement of X-ray-induced apoptosis/rapid cell death by wortmannin accompanied by increased activation of JNK/SAPK in human leukemia MOLT-4 cells. Rapid cell death/apoptosis was determined either by the dye exclusion test or by the appearance of Annexin V-positive cells and cleaved PARP fragments. Enhancement was observed only at higher concentrations of wortmannin, i.e. 1 microM or more. At these high concentrations, both DNA-PK and ATM were inhibited. X-ray-induced phosphorylation of Ser 15 of p53/TP53, accumulation of both p53/TP53 and p21/WAF1/CDKN1A, and phosphorylation of XRCC4 were all suppressed. The enhancement of apoptosis/rapid cell death by wortmannin was prevented by addition of caspase inhibitors, Z-VAD-FMK or Ac-DEVD-CHO, or by transfection and overexpression of mouse Bcl2, which is known as an anti-apoptosis protein. The requirement for a high concentration of wortmannin, i.e. 1 microM or more, indicates that inhibition of both DNA-PK and ATM was necessary for the enhanced apoptosis/rapid cell death. Phosphorylation of AKT/PKB was completely suppressed at a much lower concentration, i.e. 0.1 microM wortmannin, where no enhancement of X-ray-induced apoptosis/rapid cell death was observed. On the other hand, X-ray-induced phosphorylation of JNK and its kinase activity as well as apoptosis/rapid cell death were all significantly enhanced only at high concentrations of wortmannin, i.e. 1 microM or more. Furthermore, the extent of enhancement of both JNK phosphorylation and of apoptosis/rapid cell death by wortmannin was less in Rh1a cells, which are ceramide- and radiation-resistant variant cells compared to the parental MOLT-4 cells. Therefore, activation of the JNK pathway was considered important for the enhancement of X-ray-induced apoptosis/rapid cell death of MOLT-4 cells by wortmannin, because of the requirement for a higher concentration of wortmannin than that required for inhibition of AKT phosphorylation. The suppression of the AKT-dependent pathway by wortmannin may have some underlying role in activating the JNK pathway toward the enhancement of cell death in the current system.
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PMID:Wortmannin-enhanced X-ray-induced apoptosis of human T-cell leukemia MOLT-4 cells possibly through the JNK/SAPK pathway. 1296 28

The effects of X-rays on cell survival, apoptosis, and long-term response in the development of cell death as measured by the dye exclusion test were studied in human leukemic MOLT-4 cells (p53 wild-type) stably transfected with a mutant p53 cDNA expression vector. Cell survival, as determined from colony-forming ability, was increased in an expression level dependent manner, but the increase was partial even with the highest-expressing clone (B3). This contrasts with the prior observation that cell death and apoptosis in B3 are completely inhibited at 24 h after irradiation with 1.8 Gy of X-rays. The examination of B3 cells incubated for longer than 24 h after X-irradiation showed a delay in the induction of cell death and apoptosis. Western blot analysis revealed that the time required to reach the highest level of wild-type p53 protein in B3 was longer than the time in MOLT-4 and that the p53 may be stabilized by the phosphorylation at Ser-15. These results suggest that the introduction of mutant p53 into MOLT-4 merely delays the development of apoptosis, during which the cells could repair the damage induced by X-rays, and results in the partial increase in cell survival.
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PMID:Delayed expression of apoptosis in X-irradiated human leukemic MOLT-4 cells transfected with mutant p53. 1367 48

A post-irradiation treatment of the human leukemia cell line MOLT-4 with the antioxidant Trolox attenuated caspase-3 dependent apoptosis. The increase in the p53 expression and SAPK/JNK activation after X irradiation was also inhibited by a Trolox treatment, but the expression of BCL-2 and BAX, which would occur downstream from p53, was not changed. Studies on the effects of the intracellular calcium chelator BAPTA-AM on the induction of apoptosis and the activation of SAPK/JNK and caspase-3 proved that the chelation of calcium merely delayed the onset of radiation-induced apoptosis and the activation of SAPK/JNK and caspase-3. When the effects of the protein synthesis inhibitor cycloheximde on the apoptotic signaling pathways, including the activation of caspase family proteins and SAPK/JNK, were investigated, the expression of death receptor Fas through SAPK/JNK activation was found to be required for radiation-induced apoptosis. Finally, the relationship between the amounts of DNA dsb and induction of apoptosis was examined by irradiating BrdU-incorporated cells. An increase in DNA dsb caused by BrdU was found, but the induction of apoptosis was not enhanced. From these data, we could get no positive evidence for DNA as a target of X-rays and p53 as an indispensable factor to induced apoptosis in X-irradiated MOLT-4 cells.
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PMID:Induction of apoptosis through the activation of SAPK/JNK followed by the expression of death receptor Fas in X-irradiated cells. 1464 22


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