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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High level activation of p53-dependent transcription occurs following cellular exposure to genotoxic damaging agents such as UV-C, while ionizing radiation damage does not induce a similarly potent induction of p53-dependent gene expression. Reasoning that one of the major differences between UV-C and ionizing radiation damage is that the latter does not inhibit general transcription, we attempted to reconstitute p53-dependent gene expression in ionizing irradiated cells by co-treatment with selected transcription inhibitors that alone do not activate p53. p53-dependent transcription can be dramatically enhanced by the treatment of ionizing irradiated cells with low doses of DRB, which on its own does not induce p53 activity. The mechanism of ionizing radiation-dependent activation of p53-dependent transcription using DRB is more likely due to inhibition of gene transcription rather than prolonged DNA damage, as the non-genotoxic and general transcription inhibitor Roscovitine also synergistically activates p53 function in ionizing irradiated cells. These results identify two distinct signal transduction pathways that cooperate to fully activate p53-dependent gene expression: one responding to lesions induced by ionizing radiation and the second being a kinase pathway that regulates general RNA Polymerase II activity.
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PMID:Synergistic activation of p53-dependent transcription by two cooperating damage recognition pathways. 1095 76

Breast cancer is the second most prevalent cancer affecting Indian women. Genetic alterations of oncogenes and tumor suppressor genes were attributed to the development of breast carcinomas. In the present study, human breast tumor DNAs from untreated, non-familial, Indian patients were analysed for the presence of mutations in p53, fhit, p16INK4a/p19ARF and H-ras genes. Polymerase chain reaction-single strand conformation polymorphism and sequencing analysis were used to detect point mutations. Exons 5-8 of p53, exons 1-2 of p16INK4a, exon 2 of p19ARF, exons 5-9 of fhit gene and exons 1-2 of H-ras genes were amplified and analysed individually using exon-flanking primers. Only 12% of the tumors had mutation in p53, 8% had mutation in fhit gene and none of the tumors showed evidence for mutation in p16INK4a/p19ARF and H-ras genes. Tumor B18 exhibited two novel mutations in the p53 gene, ATGright curved arrow GTG (Metright curved arrow Val) at codon 237 and AATright curved arrow GAT (Asnright curved arrow Asp) at codon 263. Both of these mutations are hitherto unreported in breast carcinomas. Tumor B20 had a non-sense mutation CGAright curved arrow TGA (Argright curved arrow Stop) at codon 306 of p53 gene. In fhit gene, tumor B1 exhibited TTCTright curved arrow TACT mutation at intron 8 and tumor B15 had a silent mutation GAGright curved arrow GAA (Gluright curved arrow Glu) at codon 123. Our results indicate that, among the genes analysed, the p53 gene was more frequently mutated than fhit, p16INK4a/p19ARF and H-ras genes in Indian mammary tumors. Transcribable point mutations of fhit gene were found to be extremely uncommon in these tumors. Mutations in the above genes are mutually exclusive and are infrequent in fhit, p16INK4a/p19ARF and H-ras genes suggesting that these genes may not play a major role in Indian breast carcinomas. However, the significant frequency of mutations in the p53 gene suggest that p53 could be one of the genes involved in the genesis of sporadic breast carcinomas in Indian women.
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PMID:Mutation profile of the p53, fhit, p16INK4a/p19ARF and H-ras genes in Indian breast carcinomas. 1102 9

The carcinogenic plant extract aristolochic acid (AA) is thought to be the major causative agent in the development of urothelial carcinomas found in patients with Chinese herb nephropathy (CHN). These carcinomas are associated with overexpression of p53, suggesting that the p53 gene is mutated in CHN-associated urothelial malignancy. To investigate the relation between AA-DNA adduct formation and possible p53 mutations, we mapped the distribution of DNA adducts formed by the two main components of AA, aristolochic acid I (AAI) and aristolochic acid II (AAII) at single nucleotide resolution in exons 5-8 of the human p53 gene in genomic DNA. To this end, an adduct-specific polymerase arrest assay combined with a terminal transferase-dependent PCR (TD-PCR) was used to amplify DNA fragments. AAI and AAII were reacted with human mammary carcinoma (MCF-7) DNA in vitro and the major DNA adducts formed were identified by the (32)P-postlabeling method. These adducted DNAs were used as templates for TD-PCR. Sites at which DNA polymerase progress along the template was blocked were assumed to be at the nucleotide 3' to the adduct. Polymerase arrest spectra thus obtained showed a preference for reaction with purine bases in the human p53 gene for both activated compounds. For both AAs, adduct distribution was not random; the strongest signals were seen at codons 156, 158-159 and 166-167 for exon 5, at codons 196, 198-199, 202, 209, 214-215 and 220 for exon 6, at codons 234-235, 236-237 and 248-249 for exon 7 and at codons 283-284 and 290-291 for exon 8. Overall guanines at CpG sites in the p53 gene that correspond to mutational hotspots observed in many human cancers seem not to be preferential targets for AAI or II. We compared the AA-DNA binding spectrum in the p53 gene with the p53 mutational spectrum of urothelial carcinomas found in the human mutation database. No particular pattern of polymerase arrest was found that predicts AA-specific mutational hotspots in urothelial tumors of the current p53 database. Thus, AA is not a likely cause of non-CHN-related urothelial tumors.
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PMID:Sequence-specific detection of aristolochic acid-DNA adducts in the human p53 gene by terminal transferase-dependent PCR. 1115 51

Twenty-three cases of basaloid squamous cell carcinoma (BSCC) and 23 stage-matched pairs of typical squamous cell carcinoma (SCC) of the oesophagus were investigated for molecular aberrations. Polymerase chain reaction (PCR) was used to detect loss of heterozygosity at the APC, RB, and MCC gene loci, while differential PCR was carried out to detect amplification of the CDK4 gene. In addition, the level of expression of the p53 and RB proteins in the tumour tissue was assessed by immunohistochemistry. Loss of heterozygosity (LOH) at the APC and MCC loci was about twice as common in BSCC as in SCC (40% vs. 21% and 33% vs. 12%, respectively), with co-existence of LOH at both loci occurring only in BSCC. LOH frequency at the RB gene locus was not remarkably different in either BSCC or SCC (20% vs. 24%, respectively). On immunohistochemistry, accumulation of p53 protein was slightly more frequent in BSCC than in SCC (61% vs. 52%), whereas the rate of loss of RB protein expression was about equal in both types of carcinoma (9% vs. 13% BSCC and SCC, respectively). There was no detectable amplification of the CDK4 gene in either type of tumour. Although the observed differences did not achieve statistical significance, this work has further highlighted possible differences between the molecular pathogenesis of BSCC and SCC.
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PMID:Comparative analysis of basaloid and typical squamous cell carcinoma of the oesophagus: a molecular biological and immunohistochemical study. 1118 Jan 60

The prevalence and significance of genetic abnormalities in older patients with acute myeloid leukemia (AML) are unknown. Polymerase chain reactions and single-stranded conformational polymorphism analyses were used to examine 140 elderly AML patients enrolled in the Southwest Oncology Group study 9031 for FLT3, RAS, and TP53 mutations, which were found in 34%, 19%, and 9% of patients, respectively. All but one of the FLT3 (46 of 47) mutations were internal tandem duplications (ITDs) within exons 11 and 12. In the remaining case, a novel internal tandem triplication was found in exon 11. FLT3 ITDs were associated with higher white blood cell counts, higher peripheral blast percentages, normal cytogenetics, and less disease resistance. All RAS mutations (28 of 28) were missense point mutations in codons 12, 13, or 61. RAS mutations were associated with lower peripheral blast and bone marrow blast percentages. Only 2 of 47 patients with FLT3 ITDs also had a RAS mutation, indicating a significant negative association between FLT3 and RAS mutations (P =.0013). Most TP53 mutations (11 of 12) were missense point mutations in exons 5 to 8 and were associated with abnormal cytogenetics, especially abnormalities in both chromosomes 5 and 7. FLT3 and RAS mutations were not associated with inferior clinical outcomes, but TP53 mutations were associated with a worse overall survival (median 1 versus 8 months, P =.0007). These results indicate that mutations in FLT3, RAS, or TP53 are common in older patients with AML and are associated with specific AML phenotypes as defined by laboratory values, cytogenetics, and clinical outcomes. (Blood. 2001;97:3589-3595)
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PMID:FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. 1136 55

Irradiated aortic endothelial cells (EC) exhibit distinct morphological, functional, and physiological responses to ionizing radiation (IR). However, the molecular basis for these responses has not been fully characterized. Cultured bovine and rat aortic endothelial cells were exposed to single fraction doses (0-30 Gy) of gamma radiation. IR caused dose-dependent DNA strand breaks which were repaired to near baseline levels within 30 min. A dose-dependent inhibition of cell growth was noted for IR greater than 1 Gy. At doses greater than 2.5 Gy, morphologic changes consistent with apoptosis and loss of cell viability were present beginning 12-16 h after radiation, with subsequent detachment of EC from the cell monolayer. By Western blot analysis, expression of p53, gadd45, p21, and bax protein increased in a time-and dose-dependent manner; p53 expression was maximal at 3 h after IR, and gadd45, bax and p21 levels peaked at 6 h. By Reverse Transcriptase Polymerase Chain Reaction (RT-PCR), levels of p53 mRNA were not significantly increased after IR, whereas gadd45 exhibited time- and dose-dependent increase in mRNA synthesis after IR. Activation of intracellular caspases, manifest by proteolytic poly (ADP-ribose) polymerase (PARP) and lamin B cleavage, was maximal at 15 h after IR, concident with other indices of EC apoptosis, including oligonucleosomal DNA degradation, TUNEL immunostaining, and morphologic changes. The tripeptide protease inhibitor z-Val-Ala-Asp (zVAD) prevented PARP and lamin cleavage, DNA fragmentation, morphological changes, and cell detachment in irradiated EC. The combined data suggested that gamma radiation induces a dose- and time-dependent sequence of early events in cultured EC with modulate growth arrest, apoptosis, and possibly premature senescence in surviving cells.
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PMID:Early molecular changes in irradiated aortic endothelium. 1138 18

Renal transplant recipients are prone to numerous benign and malignant skin lesions. Previous work in the authors' laboratory has determined that the human papillomavirus may be the viral aetiology of these skin lesions. The p53 tumor-suppressor gene is the most frequently mutated gene in a wide range of human cancers. Here the authors describe an immunohistochemical study to evaluate the expression of p53 in benign and malignant skin lesions from renal transplant recipients and immunocompetent patients with skin cancer. The effect of p53 mutations on the expression patterns observed were examined by polymerase chain reaction-single strand conformation polymorphism analysis and direct cycle sequencing. The expression of the p53-regulated cyclin-dependant kinase inhibitor p21Waf1/Cip1 and Mdm2 was also examined in p53-positive cells. The expression of p53 in benign and malignant lesions was found to be markedly different. p53 was expressed in only 40% (6/15) of viral warts analyzed. The expression was confined to the basal layer both in the lesion and in adjacent normal skin, and the level of expression was low and only in a small number of cells (<10%). Of the cutaneous squamous cell carcinomas analyzed, 60% (9/15) showed p53 expression. Two different patterns of expression were observed. Basal layer expression in both the invasive tumor and adjacent normal skin was observed in 50% of the p53-positive squamous cell carcinomas; in the remaining 50%, p53 was expressed diffusely throughout the invasive tumor and in the basal layer of adjacent normal skin. The level of expression was high and in a large number of cells. Polymerase chain reaction-single strand conformation polymorphism analysis revealed that only one of the squamous cell carcinomas expressing p53 harbored a p53 mutation and that the accumulated p53 in the remaining tumors was wild type. No Mdm2 or p21Waf1/Cip1 expression was detected in the p53-positive squamous cell carcinomas, indicating that although the accumulated p53 is stable, it does not function effectively as a transcriptional activator. This represents a novel p53 phenotype in cutaneous squamous cell carcinoma. In addition, no correlation was seen between the presence and absence of human papillomavirus and p53 expression.
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PMID:Altered p53 expression in benign and malignant skin lesions from renal transplant recipients and immunocompetent patients with skin cancer: correlation with human papillomaviruses? 1155 22

Molecular cytogenetic and loss of heterozygosity (LOH) analyses of non-small-cell lung cancer (NSCLC) have shown frequent allelic deletions in a variety of chromosomes, such as 1p, 3p, 5q, 8p, 9p, 11p, 11q, and 17p. Allelic loss at 3p21, 9p21, and 5q21 has also been reported in premalignant epithelial lesions of the bronchus and in normal bronchial cells. These findings suggest that a tissue field of somatic genetic alterations precedes the histopathological phenotypic changes of carcinoma. LOH at chromosomal regions 3p21, 5q21, 9p21, and 17p (TP53) was looked for in the peritumoural normal bronchial cells from 30 archival surgically resected tumours. Microdissected normal bronchial cells from 20 benign cytological smears were also added to the study. Matched populations of lymphocytes, tumour cells, and normal bronchial cells adjacent to the tumour were microdissected from paraffin-embedded tissues, while matched populations of normal bronchial cells and inflammatory cells were microdissected from benign cytological smears (bronchial brushings). Polymerase chain reaction (PCR) amplification was performed utilizing the specific markers D5S346, D3S1300, D9S157, D9S171, and TP53. Within the NSCLC tumour cells, LOH was more frequently found at the 5q21 locus (72% of the informative cases), the 3p21 locus (47%), 9p21 (48%), and 17p (33%). Within the peritumoural normal bronchial cells, LOH at 5q21 was found in 37.5% of the cases, 22% showed LOH at 3p21, 27% at 9p21, and 13% at 17p (TP53). LOH was also detected in one case, in normal bronchial cells obtained from cytological smears at one locus (5q21). In conclusion, normal bronchial mucosa adjacent to NSCLC has frequent allelic losses at 3p21, 5q21, and 9p21, while LOH at these loci is unusual in normal bronchial cells obtained from cytological smears from patients with no evidence of malignancy. LOH at these loci may be present before the onset of the malignant growth. LOH studies may supplement the histopathological evaluation of bronchial cells to detect genotypic alterations in both cytological and biopsy specimens.
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PMID:3p21, 5q21, and 9p21 allelic deletions are frequently found in normal bronchial cells adjacent to non-small-cell lung cancer, while they are unusual in patients with no evidence of malignancy. 1174 74

The HIV epidemic in the Asian subcontinent has a significant impact on India. Patients with AIDS have an increased risk of developing non-Hodgkin lymphoma (NHL). In this study, we have investigated the pattern of distribution of lymphoid neoplasms and also studied the Epstein-Barr virus (EBV)-association and p53 expression in 35 HIV-positive patients from India. The biopsy samples were studied for histology and for expression of CD20, CD3, CD15, CD30, light chains, CD138, bcl-6, epithelial membrane antigen, EBV-latent membrane protein-1, and p53 protein. In situ hybridization was performed with digoxigenin-labeled anti-sense EBV-encoded nuclear RNA-1 (EBER-1) probe. Polymerase chain reaction (PCR) was performed on DNA extracted from paraffin sections for EBV-subtype analysis. The 35 cases included 7 cases of Hodgkin disease (HD), 4 cases of plasmacytoma (PL), and 24 cases of NHL. Among the cases of NHL, 3 were Burkitt lymphoma (BL), 4 were diffuse large B-cell lymphoma (DLBL) of centroblastic type (CBL), 10 were DLBL of immunoblastic type (IBL), 4 were high-grade B-cell lymphoma (unspecified) and the rest were other subtypes. EBV-association was noted in all cases of HD, 2 of 3 BL, and 3 of 10 IBL. PCR analysis of the EBNA-3C gene revealed amplimers corresponding to type A. A p53 protein overexpression was noted in 6 of 10 IBLs, 1 of 3 BLs, 2 of 3 CBLs, and 5 of 7 cases of HD. This is the first reported study of lymphoid malignancies in HIV-positive individuals from India.
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PMID:Lymphoid neoplasms in HIV-positive individuals in India. 1183 89

We describe an uncommon case of adenosquamous carcinoma arising in a Barrett esophagus in a 72-year-old white man who occasionally used alcohol, and was a nonsmoker for 34 years. Polymerase chain reaction-based microsatellite analysis was performed on the adenocarcinoma component (AC) and squamous cell carcinoma component (SC) of the tumor. The metaplastic Barrett epithelium (BE), the AC and the SC all showed loss of the same allele at 4 markers on chromosome 9p. Furthermore, the AC and the SC both showed loss of the same allele at all informative markers tested on chromosomal arms 3p, 5q, 10q, 14q, and 18q. In addition, both the SC and AC component contained the same missense mutation in the p53 tumor-suppressor gene. The only observed difference was a shift at a marker on chromosome 16q in the AC, whereas no shift was found in the BE and the SC. These findings suggest that this biphasic tumor has a monoclonal origin. The divergence presumably occurred late in the tumorigenesis of this carcinoma.
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PMID:Molecular evidence for the same clonal origin of both components of an adenosquamous Barrett carcinoma. 1187 11


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