Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:B6E4X6 (mutant p53)
 3,342 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The marked increases in p53 and p21/WAF1 levels that occur during Epstein-Barr virus (EBV) infection and the generation of immortal B lymphoblastoid cell lines (LCL) do not lead to growth arrest or apoptosis, although increasing wild-type (wt) p53 levels in EBV-infected cells by transfection or DNA damage induce these effects. We hypothesized that the concentration of p53 relative to that of LMP1 determines whether EBV-infected B cells undergo growth arrest and apoptosis. Cell cycle arrest and apoptosis were evaluated in LCL expressing varying p53 levels achieved by treating the cells with increasing concentrations of cisplatin, and we supplemented this approach with experiments in EBV-infected Burkitt's lymphoma (BL) cells transfected with a temperature-sensitive (ts) mutant human p53 and studies in LCL infected with recombinant adenoviruses expressing wt and ts mutant p53. Small increases in p53 and p21/WAF1 led to cell cycle arrest at the G2/M boundary, but not to apoptosis; moderate increases resulted in growth arrest at the G1/S boundary, also without apoptosis; and large increases also induced apoptosis. These results confirm the hypothesis and reveal unanticipated complexities in cell cycle regulation by p53.
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PMID:Levels of p53 in Epstein-Barr virus-infected cells determine cell fate: apoptosis, cell cycle arrest at the G1/S boundary without apoptosis, cell cycle arrest at the G2/M boundary without apoptosis, or unrestricted proliferation. 983 85

The proliferating cell nuclear antigen (PCNA) is a highly conserved cellular protein that functions both in DNA replication and in DNA repair. Exposure of a rat embryo fibroblast cell line (CREF cells) to gamma radiation induced simultaneous expression of PCNA with the p53 tumor suppressor protein and the cyclin-dependent kinase inhibitor p21(WAF1/Cip1). PCNA mRNA levels transiently increased in serum-starved cells exposed to ionizing radiation, an observation suggesting that the radiation-associated increase in PCNA expression could be dissociated from cell cycle progression. Irradiation of CREF cells activated a transiently expressed PCNA promoter chloramphenicol acetyltransferase construct through p53 binding sequences via a mechanism blocked by a dominant negative mutant p53. Electrophoretic mobility shift assays with nuclear extracts prepared from irradiated CREF cells produced four p53-specific DNA-protein complexes with the PCNA p53 binding site. Addition of monoclonal antibody PAb421 (p53-specific) or AC238 (specific to the transcriptional coactivator p300/CREB binding protein) to the mobility shift assay distinguished different forms of p53 that changed in relative abundance with time after irradiation. These findings suggest a complex cellular response to DNA damage in which p53 transiently activates expression of PCNA for the purpose of limited DNA repair. In a population of nongrowing cells with diminished PCNA levels, this pathway may be crucial to survival following DNA damage.
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PMID:p53-mediated regulation of proliferating cell nuclear antigen expression in cells exposed to ionizing radiation. 985 27

In this study we describe a novel putative p53-responsive gene, designated p22/PACAP response gene 1 (PRG1), recently identified as a proliferation-associated early-response gene in rats. By means of electrophoretic mobility shift assay and CAT-reporter gene assay, we could demonstrate that the p53 binding site residing in the promoter of p22/PRG1 is functional in vitro. Furthermore, in clone 6 cells expression of p22/PRG1 is induced in parallel to p21/Waf1 under conditions permitting mutant p53 to adopt wild-type configuration. An increase of p22/PRG1 transcription was also observed in gamma-irradiated rat splenocytes, which undergo p53-dependent apoptosis. Our findings demonstrate that p22/PRG1 fulfills all essential criteria as a p53 target gene and might be implicated in p53-dependent apoptosis.
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PMID:p22/PACAP response gene 1 (PRG1): a putative target gene for the tumor suppressor p53. 992 93

A murine erythroleukemic cell line (1-2-3) which expresses only the temperature-sensitive mutant p53 gene (Ala-to-Val substitution at codon 135) was established. These cells showed typical characteristics of apoptosis, when they were cultured at 32 degrees C. In this process, p53 recovered the wild-type p53 function and the expression of the p21 (waf1/cip1/sdi1), cyclin G1 and gadd45 genes was increased. However, no significant changes were detected in the expression of the mdm2, bcl-2, bax, fas and fasl genes, suggesting the existence of other genes associated with apoptosis. Genes up-regulated by p53 were screened by the mRNA differential display method. One of the up-regulated genes was identified as the elongation factor 1 alpha (EF-1 alpha) gene. EF-1 alpha is also a microtubule-severing protein. Upon the temperature-shift, the cells developed the morphology and the localization of alpha-tubulin similar to those of the cells treated with vincristine, a drug that affects microtubules. The microtubule-severing associated with up-regulation of EF-1 alpha by p53 may be a cause of the cell death. On the other hand, the function of cyclin G1 is not so clear despite the fact that 1-2-3 cells showed a significant increase of the cyclin G1 gene during the early stage of apoptosis. The yeast two-hybrid system was used to identify cyclin G1-associated proteins. One is a cytochrome c (Cyt c) oxidase subunit II (COXII). Cyclin G1 and COXII were co-immunoprecipitated from an extract of human osteosarcoma cell line that expressed high levels of cyclin G1. COX activity was also increased by temperature-shift in this cell line. The pattern of changes in COX activity was closely reflected by the expression of the cyclin G1 gene. Cyclin G1 and COXII associate physically with each other in vivo and that activation of COXII by binding to cyclin G1 upregulated by p53 may be associated with apoptosis. These two new pathways, p53-EF-1 alpha-microtubule-severing (-distortion of cytoskeleton) and p53-cyclin G1-COXII (-CytC, ATP-caspase-3 activation), may cooperate to induce apoptosis in this cell line.
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PMID:The mechanisms of death of an erythroleukemic cell line by p53: involvement of the microtubule and mitochondria. 1019 36

The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) has been shown to induce apoptosis in various tumor cell lines including human non-small cell lung carcinoma (NSCLC) cells, which are resistant to the natural all-trans retinoic acid and to many synthetic receptor-selective retinoids. Although the mechanism of this effect was not elucidated, it was found to be independent of nuclear retinoid receptors. In the present study, we analysed the mechanisms by which CD437 induces apoptosis in two human NSCLC cell lines: H460 with wild-type p53 and H1792 with mutant p53. Both cell lines underwent apoptosis after exposure to CD437, although the cell line with wild-type p53 (H460) was more sensitive to the induction of apoptosis. CD437 increased the activity of caspase in both cell lines, however, the effect was much more pronounced in the H460 cells. The caspase inhibitors (Z-DEVD-FMK and Z-VAD-FMK) suppressed CD437-induced CPP32-like caspase activation and apoptosis in both cell lines. CD437 induced the expression of the p53 gene and its target genes, p21, Bax, and Killer/DR5, only in the H460 cells. These results suggest that CD437-induced apoptosis is more extensive in NSCLC cells that express wild-type p53, possibly due to the involvement of the p53 regulated genes Killer/DR5, and Bax although CD437 can also induce apoptosis by means of a p53-independent mechanism. Both pathways of CD437-induced apoptosis appear to involve activation of CPP32-like caspase.
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PMID:Mechanisms of apoptosis induced by the synthetic retinoid CD437 in human non-small cell lung carcinoma cells. 1032 56

The Cdk inhibitor p21/WAF1 can be transcriptionally activated by wild-type p53, not by mutant p53, and functions to block cell-cycle progression in many human neoplasms. We examined the immunohistochemical expression of p53 and p21 in 35 human primary glioblastomas in relation to tumor proliferation potential as assessed by the Ki-67 labeling index (LI) and the glioblastoma apoptosis index (AI). The expression of mutant p53 was observed in 74% of glioblastomas, wild-type p53 in 18% of glioblastomas, and p21 in 57% of glioblastomas. p21 expression was seen in 15 of 26 mutant p53-positive and 2 of 4 wild p53-positive tumors. Tumor Ki-67 LI correlated neither with p53 nor with p21 expression in glioblastomas. Apoptosis was identified in all 15 glioblastomas examined, with a mean (+/-SD) Al of 1.69+/-1.54, and correlated neither with p53 (wild or mutant) nor with p21 expression. The results of the present study suggest that p53 mutation and p21 protein expression are frequent in primary glioblastoma but lack correlation with tumor proliferation potential and apoptosis. The lack of correlation between p21 and p53 also suggests that p21 in glioblastomas may be induced by a p53-independent pathway.
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PMID:Immunohistochemical analysis of p53 and p21 in human primary glioblastomas in relation to proliferative potential and apoptosis. 1032 45

Transformation of pre-B cells by Abelson murine leukemia virus (Ab-MLV) involves a balance between positive, growth-stimulatory signals from the v-Abl oncoprotein and negative regulatory cues from cellular genes. This phenomenon is reflected by the clonal selection that occurs during Ab-MLV-mediated transformation in vivo and in vitro. About 50% of all Ab-MLV-transformed pre-B cells express mutant forms of p53 as they emerge from this process, suggesting that this protein may play an important role in the transformation process. Consistent with this idea, expression of p19(Arf), a protein whose function depends on the presence of a functional p53, is required for the apoptotic crisis that characterizes primary Ab-MLV transformants. To test the role of p53 in pre-B-cell transformation directly, we examined the response of Trp53(-/-) mice to Ab-MLV. The absence of p53 shortens the latency of Abelson disease induction but does not affect the frequency of cells susceptible to Ab-MLV-induced transformation. However, primary transformants derived from the null animals bypass the apoptotic crisis that characterizes the transition from primary transformant to fully malignant cell line. These effects do not require p21(Cip-1), a major downstream target of p53; however, consistent with a role of p19(Arf), transformants expressing mutant p53 and abundant p19 retain wild-type p19 sequences.
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PMID:p53 mediates apoptotic crisis in primary Abelson virus-transformed pre-B cells. 1037 32

The human fibrosarcoma cell line, HT1080, clone H4, was used to determine if the transformation suppressive functions of p53 and Egr-1 have the same underlying mechanism. This cell line expresses only mutant p53 and no detectable Egr-1. H4 clones stably expressing Egr-1 are less transformed in proportion to the level of Egr-1 expressed, acting through the induction of the TGFbeta1 gene. Here, H4 cells and the highest Egr-1 expressing clone were transfected with a vector expressing normal human p53 to derive stable clones expressing p53. The expression of p53 in H4 cells inhibited transformed growth and reduced tumorigenicity. The effect of coexpression of both p53 and Egr-1 was additive, producing cell lines with 30% of normal growth rate and sevenfold reduced tumorigenicity compared with control lines. These results indicated that each factor may act independently by different pathways, although each additively increased the level of p21WAF1 cell cycle inhibitor. However, exposure of the H4-derived cells to UV-C irradiation produced contrasting effects. Cell cycle analyses showed that the presence of p53 was associated with loss of the G1 and S cells to apoptosis after irradiation. In contrast, the expression of Egr-1 increased entry into S/G2 phase of the cell cycle with little apoptosis via a mechanism involving elevated FAK and low caspase activities. Apoptosis was observed only in the cell lines that expressed no Egr-1, especially those expressing wt-p53, and was preceded by high caspase activity. In summary, Egr-1 suppressed transformation and counteracted apoptosis by the coordinated activation of TGFbeta1, FN, p21 and FAK, leading to enhanced cell attachment and reduced caspase activity. In the doubly expressing cell line, the survival effect of Egr-1 was dominant over the apoptotic effect of p53.
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PMID:p53 and Egr-1 additively suppress transformed growth in HT1080 cells but Egr-1 counteracts p53-dependent apoptosis. 1038 Aug 85

CD437 is a novel retinoid that can induce apoptosis in a variety of tumor cell types by an unknown mechanism. We found that CD437 up-regulated the expression of p21(WAF1/CIP1), Bax, and Killer/DR5 and induced G1 arrest and rapid apoptosis in three human non-small cell lung carcinoma cell lines with wild-type p53 but not in five cell lines with mutant p53, suggesting a role for p53 in the effects of CD437. Using H460 cells in which wild-type p53 protein was degraded by transfection of the human papillomavirus 16 E6 (HPV-16 E6) gene and H460 cells transfected with a control plasmid only, we found that CD437 increased p53, p21(WAF1/CIP1), Bax, and Killer/DR5 in the control transfectants. In contrast, the constitutive p53 protein level was suppressed, and the ability of CD437 to increase p53 and its downstream genes was compromised in E6 transfectants. In addition, CD437 induced G1 arrest and apoptosis in the control transfectants but not in the E6-transfected cells. These results indicate that p53 plays a role in CD437-induced growth inhibition and apoptosis in human non-small cell lung carcinoma cells.
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PMID:Implication of p53 in growth arrest and apoptosis induced by the synthetic retinoid CD437 in human lung cancer cells. 1038 41

Deregulation of cell cycle regulatory mechanisms leads to disruption of normal control of cell growth and may be associated with neoplastic transformation. To determine whether immortalized human cells have alterations in their cell cycle regulatory mechanisms, we analyzed cell cycle regulatory proteins in 2 immortalized human fibroblast cell lines, KMST-6 and OUMS-24/P6X, established by repeated irradiation with (60)Co gamma rays alone or mutant p53 gene transfection plus X-ray irradiation, respectively. Both the immortalized cell lines had markedly enhanced activity of cyclin A-associated kinase as compared with their normal counterparts. The high activity of cyclin A-associated kinase was well correlated with the increased expression of cyclin A mRNA and its protein. In addition, the immortalized cell lines showed significantly reduced amounts of p21(Cip1/Waf1/Sdi1), a potent inhibitor of cyclin dependent kinases. Furthermore, among the pRb family of proteins, p107 and p130, were hyperphosphorylated in both the immortalized cell lines, suggesting possible participation in upregulation of cyclin A associated kinase activity. These changes represent some important characteristics of immortalized cells.
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PMID:Enhanced activity of cyclin A-associated kinase in immortalized human fibroblasts. 1041 76


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