UNIPROT:P04637 - FACTA Search

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

The aim of this study was to study the protein expression of six proto-oncogenes (epidermal growth factor receptor (EGFR), c-fms, c-myc, c-kit, c-erbB-2 and pan-ras) and one tumour suppressor gene (TP53), by immunohistochemical staining of normal cervical stratified squamous epithelium and cervical intra-epithelial neoplasia (CIN). Paraffin sections of 45 normal cervical specimens, 38 CIN grade one (CIN1), 37 CIN2 and 43 CIN3 were studied. An immunohistochemical (IHC) score was derived from the intensity of staining and the percentages of cells stained. In normal cervical specimens, a higher IHC score was found with EGFR and c-fms in superficial (S), intermediate (I) and parabasal (PB) cells compared with basal cells. In contrast, a higher IHC score was found with c-erbB-2 in basal cells in normal cervical specimens. Dysplastic cells in CIN had a higher IHC score with c-myc and c-erbB-2 than normal S/I and PB cells. Dysplastic cells had a higher score with EGFR than normal basal cells. However, a higher IHC score with EGFR and c-fms was found in normal S/I cells than dysplastic cells. These findings suggested that EGFR and c-fms were activated in more differentiated normal cells but were less active in less differentiated normal basal cells. However, EGFR was reactivated in dysplastic cells. Meanwhile, c-erbB-2 was activated in less differentiated normal basal cells and dysplastic cells, and was less active in differentiated normal cells. c-myc was activated in dysplastic cells. c-fms was more active in more differentiated normal cells and was not activated in less differentiated or dysplastic cells. c-kit, pan-ras and TP53 were not activated in normal nor dysplastic cervical cells. These results suggest EGFR, c-erbB-2 and c-myc may be important proto-oncogenes in CIN and that antibodies or anti-genes targeted against them may alter the progress of CIN to invasive cancer.
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PMID:Proto-oncogenes and p53 protein expression in normal cervical stratified squamous epithelium and cervical intra-epithelial neoplasia. 1067 85

Human papillomavirus infection is postulated to be a major risk factor for cervical cancer, while more recent data have stressed the clinical significance of telomerase expression during tumorigenesis. This study therefore looked for any relationship between telomerase expression, presence of human papillomavirus (HPV) and expression of the high-risk HPV E6 protein at various phases of tumor progression in the uterine cervix. In addition, accumulation of the p53 protein and total tissue proliferative fraction were also studied. Telomerase was detected using a modified TRAP (telomerase repeat amplification protocol) assay. Expression of p53, Ki 67 and E6 protein was evaluated by immunocytochemistry. Presence of mutant p53 was detected using a mutant-specific ELISA. Type of HPV infection was determined by polymerase chain reaction and Southern blot using type-specific primers and probes. There was a significant correlation between the expression of telomerase with histological grade (r = 0.646, p = 0.00003). Fisher's exact test analysis revealed that the odds ratio of a tissue sample expressing telomerase being a case (high-grade squamous intraepithelial lesion or invasive cancer) was 28.93 (p = 0.0001, 95% CI: 7.22, to 115.94). High-risk HPV-infected tissues and those expressing E6 showed increased telomerase expression (r = 0.555, p = 0.00001). Similarly, accumulation of p53 protein and increased cell proliferation (Ki 67 index) also correlated to the presence of telomerase (r = 0.661, p = 0.000004 for p53 and r = 0.647, p = 0.000003 for Ki 67). There was no correlation between telomerase expression and presence of p53 mutation. Activation of telomerase thus appears to be associated with high-risk-HPV infection, accumulation of inactive p53 protein and increased cell proliferation in cervical lesions.
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PMID:Telomerase, p53 and human papillomavirus infection in the uterine cervix. 1075 56

Esophageal squamous cell carcinoma (ESCC) is a frequent form of cancer that shows striking variations in geographic distribution, reflecting exposure to specific environmental factors that are still poorly defined. ESCC develops as the result of a sequence of histopathological changes that typically involves esophagitis, atrophy, mild to severe dysplasia, carcinoma in situ and finally, invasive cancer. Genetic changes associated with the development of ESCC include mutation of the p53 gene, disruption of cell-cycle control in G1 by several mechanisms (inactivation of p16MTS1, amplification of Cyclin D1, alterations of RB), activation of oncogenes (e.g., EGFR, c-MYC) and inactivation of several tumor suppressor genes. Loss of heterozygosity on chromosome 17q25 has been linked with tylosis, a rare autosomal dominant syndrome associated with high predisposition to ESCC. Whether this locus is also involved in sporadic ESCC remains to be elucidated. Chronic esophagitis is a frequent occurrence in populations at high risk of ESCC. These lesions often show focal accumulation of p53 protein and in some instances, patches of positive cells in esophagitis area at the margins of tumors were found to contain a mutation in the p53 gene. This observation is consistent with field cancerization in the esophagus and suggests that esophagitis may represent an interesting target for early detection of ESCC as well as for intervention strategies.
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PMID:Genetic steps in the development of squamous cell carcinoma of the esophagus. 1076 43

Carcinogenesis is characterized by deregulation of the cell cycle. Although p53 is still the most important cell-cycle regulator in human malignancies, there is an increased body of evidence indicating that the aberrant expression of cyclins and cyclin-dependent kinase (CDK) inhibitors is considered as one of the most important events in malignant transformation of various human cancers. Among these cell-cycle regulators, the role of cyclin E and p27(KIP1) in the tumorigenesis of the uterine cervix has been poorly defined. Using formalin-fixed, paraffin-embedded cervical tissues, we investigated the expression of cyclin E and p27(KIP1) by immunohistochemistry, and human papillomavirus (HPV) types 16 and 18 by nested polymerase chain reaction (PCR) in 22 control cases, 23 cases with cervical intraepithelial neoplasia (CIN), and 45 patients with invasive cervical carcinoma (ICC). The p27 index (P27I) was significantly lower in patients with ICC and CIN compared to those with a normal cervix. Patients with either invasive cancer or CIN were found to have a significantly higher cyclin E index (CEI) than the controls (P<0.05). Our results were consistent with the concept that the deregulated expression of cyclin E and p27(KIP1) may play an important role in the neoplastic transformation of cervical carcinoma.
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PMID:Expression of cyclin E and p27(KIP1) in cervical carcinoma. 1077 28

P53 allelic polymorphism at codon 72 has been studied as a possible predisposing factor for cervical carcinogenesis with inconsistent results. Storey and colleagues recently published the interesting finding of a 7-fold increased risk for cervical cancer in women homozygous for the arginine allele at codon 72. This stimulated a number of independent investigations, the majority of which found no association of cervical cancer and arginine homozygosity. With the use of a modified Storey method for determining codon 72 allelotypes, DNA was examined from 431 microdissected, formalin-fixed, archival cervical conization specimens ranging from low-grade squamous lesions to invasive cancer. An alternative independent method using restriction fragment length polymorphism analysis was performed on all arginine homozygotes and all indeterminate cases for confirmation and final allelotype assignment. With the use of Storey's method alone, logistic regression suggested an association (odds ratio, 1.42) between arginine homozygosity and invasive disease. However, with the use of the combined method for accurate allelotyping, this trend disappeared (odds ratio, 1.00), the discordance was clearly resolvable as being due to methodologic variables. With the use of two separate methods for codon 72 allelotyping and accounting for a number of the issues raised in previously published reports, there is no increased risk for invasive cervical cancer associated with arginine homozygosity at codon 72 of p53.
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PMID:Polymorphism at codon 72 of p53 is not associated with cervical cancer risk. 1078 2

In 1998, Storey and co-workers suggested that individuals homozygous for arginine (Arg) at codon 72 of the p53 gene are about seven times more susceptible to human papillomavirus (HPV)-related carcinogenesis than heterozygotes. Since then, several studies from Northern Europe, Japan and the USA have failed to demonstrate a similar correlation. By contrast, a study in Brazil as well as one recent study in Italian and Swedish populations showed strong positive associations. We examined the frequency of p53 codon 72 polymorphism in samples from both invasive and intra-epithelial cervical neoplasias (CIN), and compared them with samples from healthy controls. All 88 samples came from women with a Greek ethnic background. Tissue specimens were collected from archival material with histologically diagnosed low-grade CIN (LGCIN), high-grade CIN (HGCIN) or cervical cancer (CxCa). As a control, we used cellular material newly collected by cytobrush from the cervices of 30 healthy women with normal cytological and colposcopical examinations. p53 Arg homozygosity (Arg/Arg) alone was associated with four-, six- or eight-fold increased risks for LGCIN, HGCIN or invasive cancer, respectively. The frequency of the p53Arg/Arg genotype and of the proline (Pro) allele showed significant linear trends according to the degree of severity of the lesion (P = 0.0007 and P = 0.0009, respectively). Exclusion of the ten HPV16/18-negative cases did not substantially alter the Arg/Arg frequency among the groups nor the significant linear trend. Our results confirm the initial findings of Storey and co-workers, as well as the data of the Brazilian and the recent European study, but do not accord with those of the other aforementioned studies. Variations in ethnic background, laboratory performance, verification of the HPV status, definition of controls, and sample size are the most plausible explanations for this controversy. In all our samples, the distribution of the p53 alleles fits the Hardy-Weinberg equilibrium and the 0.48 frequency of the Pro allele in our controls accords well with the percentages previously reported for different ethnic groups as characteristic of the assumed north-south cline. Some authors assert that the discrepancy in the results could not be attributed to differences in the methods; however, the Brazilian study emphasized the effect of inter-laboratory variation in detecting the association between p53 polymorphism and cervical cancer. Regarding the control group, our samples were only from women with a cytologically and colposcopically benign cervical epithelium. We think that simply choosing 'normal volunteers' for collecting control DNA blood samples without knowing the status of their cervical epithelium is indeed a possible source of bias. Finally, it is very unlikely that loss of heterozygosity at the p53 locus could be a factor interfering with the allelotype distribution. Our present small study results, which suggest a biologically relevant association, provide strong evidence that homozygous arginine at codon 72 of p53 may confer a higher susceptibility to HPV-associated intra-epithelial and invasive cervical neoplasia.
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PMID:p53 codon 72 polymorphism and risk of intra-epithelial and invasive cervical neoplasia in Greek women. 1083 May 78

Serum autoantibodies against the p53 protein (p53 AAb) were analysed with a newly developed enzyme-linked immunosorbent assay (ELISA) based on highly purified and renatured p53. In a hospital-based cohort study, preoperative sera from 113 patients with ovarian cancer, 15 patients with borderline tumours and 117 patients with benign tumours of the ovaries were studied. The prevalence of p53 AAb in patients with invasive cancer was 19% (21/113). No p53 AAb were found in patients with borderline lesions or benign tumours. The ELISA had a specificity for malignancy of 99% (1 of 117; false-positive from a patient with severe diabetes mellitus) and a likelihood ratio (LR+) for a positive test result of 21.7 (elevated CA125 and malignancy: LR+ 3.7). p53 AAb were only detectable in patients with immunohistochemical staining of nuclear p53 in the tumour (P = 0.006). Presence of p53 AAb positively correlated with tumour stage (P = 0.034) and grade (P = 0.009). Kaplan-Meier analysis showed both a shortened overall survival (P = 0.0016, log-rank) and relapse-free survival (P = 0.055) for p53 AAb-positive patients (median follow-up 22 months). High titres related to even worse prognosis. p53 AAb independently related to poor survival adjusting for stage (P = 0.026), grade (P = 0.029) and residual disease after surgery (P = 0.005). Preoperative findings of adnexal mass with serum p53 AAb are strongly suggestive of an aggressive invasive ovarian cancer.
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PMID:Autoimmunity against p53 predicts invasive cancer with poor survival in patients with an ovarian mass. 1104 59

The phase II glutathione S-transferases (GSTs) GSTT1, GSTM1 and GSTP1 catalyse glutathione-mediated reduction of exogenous and endogenous electrophiles. These GSTs have broad and overlapping substrate specificities and it has been hypothesized that allelic variants associated with less effective detoxification of potential carcinogens may confer an increased susceptibility to cancer. To assess the role of GST gene variants in ovarian cancer development, we screened 285 epithelial ovarian cancer cases and 299 unaffected controls for the GSTT1 deletion (null) variant, the GSTM1 deletion (null) variant and the GSTP1 codon 104 A-->G Ile-->Val amino acid substitution variant. The frequencies of the GSTT1, GSTM1 and GSTP1 polymorphic variants did not vary with tumour behaviour (low malignant potential or invasive) or p53 immunohistochemical status. There was a suggestion that ovarian cancers of the endometrioid or clear cell histological subtype had a higher frequency of the GSTT1 and GSTM1 deletion genotype than other histological subgroups. The GSTT1, GSTM1 and GSTP1 genotype distributions did not differ significantly between unaffected controls and ovarian cancer cases (overall or invasive cancers only). However, the GSTM1 null genotype was associated with increased risk of endometrioid/clear cell invasive cancer [age-adjusted OR (95% CI) = 2.04 (1.01-4.09), P = 0.05], suggesting that deletion of GSTM1 may increase the risk of ovarian cancer of these histological subtypes specifically. This marginally significant finding will require verification by independent studies.
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PMID:Polymorphisms at the glutathione S-transferase GSTM1, GSTT1 and GSTP1 loci: risk of ovarian cancer by histological subtype. 1115 43

Oral squamous cell cancers (OSCCs) have a high local recurrence rate, partly due to problems in the recognition of minimal residual disease. The use of molecular markers is shown to increase the sensitivity of detection of residual malignant cells in tumour margins of OSCC. p53 immunohistochemistry was combined with in situ hybridization for chromosomes 1 and 7 to determine the presence of genetically unstable cells in resection specimens of OSCC containing invasive cancer. An increased frequency of genetically aberrant cells was observed, as detected by p53 overexpression and/or aneusomy, with histological progression of normal mucosa via hyperplasia to dysplasia. Of clinical importance was the finding that 11 of 20 resection margins, all of which were initially diagnosed as being tumour-free, were found to contain genetically aberrant (pre)malignant cells. In these areas, closer histological examination of the genetically aberrant compartment within these margins often also revealed small dysplastic areas that were missed in the initial diagnosis, showing that this genetic approach can assist in diagnosis.
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PMID:Mapping of resection margins of oral cancer for p53 overexpression and chromosome instability to detect residual (pre)malignant cells. 1116 17

Aberrant methylation in the CpG sites located in the promoter region of several tumor suppressor genes has been reported in various types of cancers. However, the methylation status of the p53 promoter has not been clearly determined and no information is available on its role in breast cancer. The aim of the study was to determine the presence and timing of the methylation of CpG sites in the p53 promoter, in the progression from ductal carcinoma in situ to invasive cancer. We also explored the correlation between the CpG methylation of the p53 promoter and p53 mutation during the progression of breast cancer. The corresponding lesions of both the invasive and noninvasive types were microdissected in paraffin-embedded tissue of 26 breast carcinomas. Bisulfite-modified DNA sequencing for methylation status in the p53 promoter was carried out, and double-strand DNA sequencing was performed in the promoter region and exons 4 to 9 of the p53 gene. CpG site methylation in the p53 promoter was detected in three cases (11.5%). Two noninvasive and three invasive lesions harbored CpG methylation in the p53 promoter. Methylations in more than one site were observed in three lesions, all of which contained methylation in two sites. The methylated CpG sites were located near the AP1 and YY-1 binding sites and at the YY-1 binding site. The p53 mutation was not found in the lesions where methylation in p53 promoter region was evident. In 16 cases (61.5%), neither methylation nor p53 mutation was detected. We conclude that the methylation in the p53 promoter region is found in the breast cancer irrespective of the status of invasion, and that the hypermethylation in the p53 promoter region is an alternative pathway to tumorigenesis where there is no p53 gene mutation.
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PMID:Methylation in the p53 promoter is a supplementary route to breast carcinogenesis: correlation between CpG methylation in the p53 promoter and the mutation of the p53 gene in the progression from ductal carcinoma in situ to invasive ductal carcinoma. 1130 77

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