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)

Human malignant gliomas (glioblastomas and anaplastic astrocytomas) are the most frequent brain tumors and are associated with a variety of genetic alterations including retinoblastoma (RB) and p53 gene mutations, loss of interferon alpha and beta (IFNA, IFNB) genes and lack of O6-methylguanine-DNA methyltransferase (MGMT) expression. Yet, in the studies performed to date, the relationship between these alterations has not been addressed. In this report, we have studied gene expression in 29 malignant glioma cell lines and have determined that, although loss of the interferon genes and loss of RB, p53 and MGMT mRNAs are frequent events, combinations of genetic alterations involving these four proven or putative tumor-suppressor genes are relatively infrequent. The exception was loss of RB mRNA, which may be associated with lack of MGMT mRNA.
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PMID:Lack of expression of tumor-suppressor genes in human malignant glioma cell lines. 150 94

A great deal of the energy and time of a cell is invested in DNA repair activities. The first step in DNA repair pathways is recognition of the lesion on the DNA. The classical lesion-recognizing proteins interact with other repair proteins to form multiprotein complexes most notable of which are those that function in Nucleotide Excision Repair (NER). Proteins involved in lesion recognition include HMG1 and 2 recognizing cisplatin adducts but also maintaining active nucleosome structures and interacting with loops in cruciforms; HMG-box nuclear proteins; XPA and XPC lacking in xeroderma pigmentosum patients and involved in lesion recognition during NER; p53 recognizing strand breaks and insertion/deletion mismatches and causing arrest in the cell cycle; MSH2 mismatch repair protein identified as the human colon cancer gene product; and others including the transcription factor YB-1 that binds to depurinated DNA with a higher affinity compared with undamaged DNA. Other type of lesion-recognizing proteins are also repair enzymes like the O(6)-methylguanine-DNA methyltransferase and DNA glycosylases. Lesion recognition is an important process and might be the rate-limiting step in the overall repair process.
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PMID:DNA lesion-recognizing proteins and the p53 connection. 861 13

High-level expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) correlates with cellular resistance to the chloroethylnitrosourea (CENU) class of alkylating agents. Consequently, tumors expressing low levels of MGMT are sensitive to CENU chemotherapy, and any mechanism that can be used to reduce MGMT levels could sensitize resistant tumors. We have demonstrated that transient transfection of wild-type, but not mutant, p53 protein into a p53-null cell line, Saos-2, suppresses MGMT promoter activity in a reporter gene system. In addition, following a 24-h transduction of IMR90 fibroblasts with a wild-type p53-adenoviral vector, endogenous MGMT protein is down-regulated and is no longer detectable 5 days following infection. Because p53 is inducible by ionizing radiation, we propose that existing cancer therapy regimens that combine radiotherapy with CENU chemotherapy may be improved by altering scheduling and allowing enough time between the two therapies for the relatively stable MGMT protein to degrade.
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PMID:Wild-type p53 suppresses transcription of the human O6-methylguanine-DNA methyltransferase gene. 861 46

Extracts prepared from tissue specimens of normal, non-tumourous human buccal mucosa, and cultured buccal epithelial cells and fibroblasts, exhibited O6-methylguanine-DNA methyltransferase (MGMT) activity by catalysing the repair of the premutagenic O6-methylguanine lesion in isolated DNA with rates of 0.2 to 0.3 pmol/mg protein. An SV40 T antigen-immortalized buccal epithelial cell line termed SVpgC2a and a buccal squamous carcinoma line termed SqCC/Y1, both of which lack normal tumour suppressor gene p53 function, exhibited about 50 and 10% of the MGMT activity of normal cells, respectively. The normal, experimentally transformed and tumourous buccal cell types showed MGMT mRNA levels which correlated with their respective levels of MGMT activity. Exposure of buccal cell cultures to various organic or water-based extracts of products related to the use of tobacco and betel quid, decreased both cell survival (measured by reduction of tetrazolium dye) and MGMT activity (measured subsequently to the exposures in cellular extracts). Organic extracts of bidi smoke condensate and betel leaf showed higher potency than those of tobacco and snuff. An aqueous snuff extract also decreased both parameters, whereas an aqueous areca nut extract was without effect. The well-established sulph-hydryl-reactive agent Hg2+, a corrosion product of dental amalgam, served as a positive control and decreased MGMT activity following treatment of cells within a range of 1-10 microM. Taken together, significant MGMT activities were demonstrated in buccal tissue specimens and in the major buccal mucosal cell types in vitro. Lower than normal MGMT activity in two transformed buccal epithelial cell lines correlated with decreased MGMT mRNA and lack of functional p53. Finally, in vitro experiments suggested the potential inhibition of buccal mucosal MGMT activity by complex mixtures present in the saliva of tobacco and betel nut chewers.
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PMID:O6-methylguanine-DNA methyltransferase activity in human buccal mucosal tissue and cell cultures. Complex mixtures related to habitual use of tobacco and betel quid inhibit the activity in vitro. 936 96

O6-methylguanine is known as one of the major premutagenic lesions in the human and rodent carcinogenesis process. O6-methylguanine-DNA methyltransferase (MGMT), which repairs methylated guanine bases, might prevent the G:C to A:T transition, and transgenic mice carrying this MGMT gene have been reported to be less sensitive to the carcinogenicity of certain alkylating agents. Here we utilized MGMT transgenic mice to assess the significance of O6-methylguanine formation during urinary bladder carcinogenesis. In experiment 1, 100 and 60 ppm N-butyl-N(4-hydroxybutyl)nitrosamine was given for 20 weeks to transgenic and non-transgenic mice in their drinking water. The incidences of urinary bladder carcinomas were not different between transgenic mice and non-transgenic mice. The mutational spectrum of the p53 gene was evaluated by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing. The pattern of p53 mutations of transgenic and non-transgenic mice did not differ, and the frequencies of mutations were 40% and 42%, respectively. G:C to A:T transition mutations were particularly infrequent (1 of 14 mutations, 7%). In experiment 2, N-methyl-N-nitrosourea, which might induce O6-methylguanine in affected alleles, was given once a week, 3 times (total 5 mg) by direct instillation into the urinary bladder through an abdominal incision. No significant neoplastic lesions were detected, although the experiment was limited by severe toxicity of the treatment. p53 immunostaining was done and there was no difference in transgenic and non-transgenic mice. These results suggest that O6-methylguanine formation might not be a significant mutational factor in these mouse urinary bladder carcinogenesis models.
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PMID:Possible rare involvement of O6-methylguanine formation as a significant mutational factor in mouse urinary bladder carcinogenesis models. 972 94

Transgenic systems, both cell lines and mice with gain or loss of function, are being used in order to modulate the expression of DNA repair proteins, thus allowing to assess their contribution to the defense against genotoxic mutagens and carcinogens. In this review, questions have been addressed concerning the use of transgenic systems in elucidating critical primary DNA lesions, their conversion into genotoxic endpoints, low-dose effects, and the relative contribution of individual cellular functions in defense. It has been shown that the repair protein alkyltransferase (MGMT) is decisive for protection against methylating and chloroethylating compounds. Protection pertains also to tumor formation, as revealed by the response of MGMT transgenic and knockout mice. Overexpression of genes involved in base excision repair (N-methylpurine-DNA glycosylase, apurinic endonuclease, DNA polymerase beta) is in most cases not beneficial in increasing the protection level, whereas their down-modulation or inactivation increases cellular sensitivity. This indicates that non-repaired base N-alkylation lesions and/or repair intermediates possess genotoxic potential. Modulation of mismatch repair and poly(ADP)ribosyl transferase has also been shown to affect the cellular response to alkylating agents. Furthermore, the role of Fos, Jun and p53 in cellular defense against alkylating mutagens is discussed.
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PMID:Transgenic systems in studies on genotoxicity of alkylating agents: critical lesions, thresholds and defense mechanisms. 974 64

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is inducible by genotoxic stress. MGMT induction results from transcriptional activation of the MGMT gene which is a specific response to DNA damage. A possible factor involved in triggering MGMT induction might be p53, because both p53 and MGMT are activated by DNA breaks. To study the effect of p53 on induction of the MGMT gene, we compared the presence of functional wild-type (wt) and mutant p53 with MGMT expression level in various mouse fibroblasts and rat hepatoma cell lines upon genotoxic treatment. Cells which responded to ionizing radiation (IR) by MGMT induction displayed functional p53, whereas in cells not expressing wt p53, MGMT induction was not observed. Also, the cloned MGMT promoter was inducible by IR upon transfection into p53 wt cells, but not in cells deficient for p53. Thus, expression of wt p53 appears to be required for induction of MGMT mRNA and protein by IR. On the other hand, transfection of a MGMT-promoter-CAT construct together with p53 (either wt or mutant) in cells expressing wt p53 markedly reduced the basal activity of the MGMT promoter whereas cotransfection with a p53 antisense construct slightly increased MGMT promoter activity. Furthermore, cotransfection of MGMT promoter with wt or mutant p53 in p53 wt cells reduced radiation evoked MGMT promoter induction. Thus, transfection mediated high level expression of p53 has inhibitory effect both on basal MGMT promoter activity and its activation by IR. The results give evidence for involvement of p53 in DNA damage-induced MGMT promoter activation.
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PMID:p53 is involved in regulation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) by DNA damaging agents. 978 1

In a panel of 16 human ovarian tumours transplanted in nude mice, the expression of genes involved in cell cycle regulation and in response to drug treatment were characterised. In the 16 tumours analysed we could not detect overexpression of Erb-B2 oncogene while expression of MDR1 mRNA was not detected in 11/15 samples and was low in 4/15 tumours. Only three tumours had mutations in the p53 gene exons 5-8 and one of these mutations did not result in any amino acid alteration. The levels of mRNA for cyclins A, D1 and E were heterogeneous with some tumours expressing high levels and others not expressing them at all. The same was found for the cyclin dependent kinases (CDK) CDK2 and CDK4 and for CDK inhibitors p21/WAF1, p27/KIP1 and p16/CDKN2. Two genes belonging to the nucleotide excision repair, ERCC1 and ERCC3 were detectable in all the samples examined, as were the genes MGMT and MAG, also involved in DNA repair. The data indicate a heterogeneity in the expression of genes considered to be involved in the cellular responses to cytotoxic drug treatment and indicate the possibility of using these tumour models to test specifically molecules with a defined mechanism of action.
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PMID:Molecular characterisation of a panel of human ovarian carcinoma xenografts. 984 28

The DNA-repair protein O(6)-methylguanine-DNA methyltransferase (alkyltransferase; MGMT) is a major determinant of resistance of cells to various alkylating cytostatic drugs. Its expression in tissues is highly variable, indicating complex regulatory mechanisms involved. Transfection-mediated expression of wild-type p53 has been shown to negatively regulate basal promoter activity of MGMT in vitro. To elucidate whether p53 is involved in regulation of MGMT in tumor tissue, we examined MGMT expression and the p53 status of 140 primary ovarian carcinomas and analyzed the data as to the correlation between MGMT and p53, as well as the survival response of the patients after chemotherapy. We show that MGMT expression is highly variable in ovarian carcinomas, ranging from zero level up to 2500 fmol/mg protein. MGMT activity was significantly lower in tumors with wild-type p53 (p53wt) than in tumors with mutant p53 (p53mt) (p = 0.045). As expected, the percentage of tumors with p53mt increased with increasing histologic grade of the tumors. Thus, p53mt was observed in 4, 45 and 64% of grades 1, 2 and 3 tumors, respectively (p = 0.001). Increase in p53mt was accompanied by an increase in MGMT activity, which was, on average, 460 +/- 66, 624 +/- 63 and 662 +/- 60 fmol/mg protein in grades 1, 2 and 3 tumors, respectively (p = 0.047). In addition, MGMT activity as well as p53mt were associated with the FIGO stage of the tumors. Mean MGMT activity was 472 +/- 48 fmol/mg for patients with FIGO stages I and II, as compared with 675 +/- 50 fmol/mg for patients with FIGO stages III and IV, (p = 0.0179). The percentage of p53mt was 27% and 54% in ovarian tumors with FIGO stages I/II and FIGO stages III/IV, respectively (p = 0.004). Thus, progression of ovarian tumors was clearly associated with increase of both MGMT activity and the percentage of p53mt. In tumors expressing low MGMT (<100 fmol/mg), p53mt was very rarely found. No significant association was observed between MGMT level in ovarian carcinomas and the survival of patients treated with cyclophosphamide and carboplatin. On the other hand, a clear correlation was found between histological type, grading, residual tumor mass and p53wt expression and duration of the patient's survival. The finding that p53wt expression was associated with low MGMT level in primary ovarian cancer supports the view that down-regulation of basal MGMT promoter activity by p53wt is also relevant in tumor cells in vivo. Int. J. Cancer (Pred. Oncol.) 84:388-395, 1999.
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PMID:Activity of O(6)-methylguanine-DNA methyltransferase in relation to p53 status and therapeutic response in ovarian cancer. 1040 91

Repair of cytotoxic DNA damage by O(6)-methylguanine-DNA methyltransferase (MGMT) is a potentially important factor of chemoresistance to chloroethylnitrosoureas (CENUs), commonly used in the treatment of glioblastoma multiforme (GBM). The value of p53 as a prognostic factor in GBMs remains unclear, but a possible relationship between MGMT gene expression and p53 has been suggested. To further examine these GBM characteristics in vivo, we assessed MGMT gene expression using semi-quantitative RT-PCR and p53 alteration by immuno-histochemistry on a series of 39 GBMs. MGMT gene expression was inversely correlated with age (p < 0.03), consistent with the results of others. Interestingly, tumors from male patients had higher MGMT mRNA amounts than tumors from female patients (p < 0.03). No prognostic implication was observed either for MGMT gene expression or for p53 accumulation. However, MGMT gene expression was significantly lower in p53-altered GBM, regardless of the percentage of positive cells (p < 0.01). Our observation suggests that in human glial tumors, a low level of MGMT gene expression might promote p53 alteration, probably via mutation of its gene. Int. J. Cancer (Pred. Oncol.) 84:416-420, 1999.
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PMID:O(6)-methylguanine-DNA methyltransferase gene (MGMT) expression in human glioblastomas in relation to patient characteristics and p53 accumulation. 1040 96


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