Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P53 is a tumor suppressor gene that has been implicated in the molecular genetics of many human malignancies. Nucleotide alterations, most commonly single point mutations, have been shown not only to abrogate the p53 suppressor function but also to contribute to the transformed phenotype. We report the detection of a p53 gene mutation in clinical specimens of a patient with relapsing prostate adenocarcinoma 14 years after definitive external beam radiation. The techniques of single strand conformation polymorphism analysis and direct sequencing of polymerase chain reaction generated products were used for this study. Analysis of tissue from different locations of the primary tumor revealed intratumoral molecular heterogeneity; the mutation was absent in 1 area but present in another. Tumor from a regional lymph node metastasis harbored the identical p53 mutation. Furthermore, an additional genetic alteration, an allelic loss on chromosome 17p but not including the p53 gene, was observed only in the metastatic tissue. These observations in clinical specimens of primary and metastatic sites provide evidence for the association of the p53 gene in the progression of human prostate carcinoma.
 ...
PMID:Alterations of the P53 gene are associated with the progression of a human prostate carcinoma. 134 85

Mutations in the p53 gene were analyzed in 40 gliomas using the single strand conformation polymorphism assay together with restriction fragment length polymorphism analysis to assess loss of heterozygosity for 17p alleles in the same tumors. Mutations occurred in 40% of the gliomas and were found in exons 4-8 of the p53 gene. G:C to T:A transversions, which occur in high frequency in some lung (greater than 50%), liver (greater than 80%), breast (30%), and esophageal cancers (25%), were noted in greater than 25% of the gliomas studied here. These transversions were clustered in exon 5 from codons 156 to 168, a region of the p53 gene not previously associated with a high frequency of mutation, and may represent a new hot spot for mutations in certain cancers. The majority of gliomas (27 of 38) analyzed here retained both 17p alleles. The frequency of p53 mutations was 37% in this group of tumors and increased to 64% in tumors with one 17p allele. Allelic loss for chromosome 17p occurred in 4 of 11 gliomas independently of mutations in the p53 gene. Absence of p53 mutations in 36% of the tumors with one 17p allele suggests that a tumor suppressor gene other than p53 may be located on chromosome 17p and involved in progression to malignancy of some gliomas.
Cancer Res 1992 Mar 15
PMID:p53 mutations in human malignant gliomas: comparison of loss of heterozygosity with mutation frequency. 134 52

p53 is a nuclear phosphoprotein which controls normal cell growth. Normal p53 protein is undetectable by standard immunohistochemical staining and the over-expression found in neoplastic cells correlates with the presence of point mutations of evolutionary conserved regions of the p53 gene. We examined the expression of p53 protein in a series of 36 colorectal adenomas (13 tubular, 17 tubulovillous, 6 villous) showing different degrees of dysplasia (11 mild, 19 moderate, 6 severe), 11 moderately differentiated adenocarcinomas (6 Duke's A, 4 Duke's B, 1 Duke's C) and 5 metaplastic polyps using the polyclonal antibody CM1 which recognises p53 protein in conventionally fixed and processed histological material. We found that 15 out of 36 colorectal adenomas showed p53 immunoreactivity, although in 4 positive cases (26%) the staining was very focal (less than 0.1% positive cells). More than 80% of severely dysplastic adenomas showed strong p53 immunoreactivity and this over-expression was correlated with increased cell proliferative rate as detected by the proliferating-cell-nuclear-antigen (PCNA) staining. p53 nuclear staining was also seen in 8 out of 11 (65%) colorectal adenocarcinomas as previously shown. Our data suggest that the p53 gene mutation, with the subsequent over-expression of the protein, occurs in colorectal adenomas and may therefore be a fundamental genetic event underlying the dysplasia and loss of proliferative control that are characteristic of adenomas with malignant potential.
Int J Cancer 1992 Mar 12
PMID:Over-expression of p53 nuclear oncoprotein in colorectal adenomas. 134 13

Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.
 ...
PMID:Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer. 134 43

Recent studies have demonstrated that allelic losses at chromosome 17p are associated with the genesis of a wide variety of human cancers. In order to assess whether the rearrangement of chromosome 17p was responsible for the genesis of renal cell carcinoma (RCC), we used restriction fragment length polymorphism analysis of chromosome 17p. We studied 48 RCCs, including 6 metastatic RCCs, from 43 patients with 5 polymorphic probes to loci within or near the p53 gene. Allelic losses at chromosome 17p were detected in only 6 of the 36 informative cases (17%), and no definitive correlation was demonstrated between allelic losses at 17p and the tumor stages. The 6 RCCs with allelic losses at 17p were histopathologically classified as a clear cell type in one, a mixed cell type in one, and granular cell types in the other four cases. Allelic losses at 17p in the clear cell type of RCC were infrequent (6%, 1 of 18), and were not detected even in the metastatic tumor from a highly advanced case. This finding suggests that allelic losses at 17p could be random genetic rearrangements in the case of the clear cell type of RCC. On the other hand, allelic losses at 17p in the granular cell type of RCC were demonstrated with a significantly higher frequency (44%, 4 of 9). We previously reported that allelic losses at 3p were specific to the clear cell type of RCC (Ogawa et al., Cancer Res., 51:949-953, 1991). Examination of the association of allelic losses at 17p with those at 3p revealed that none of 5 informative RCCs with allelic losses at 17p showed allelic losses at 3p. Conversely, 17 of 25 informative RCCs with retention of 17p alleles lost alleles at 3p. Thus, an inverse relationship was demonstrated with statistical significance (P less than 0.01). These data suggest that the types of rearrangement on chromosome 17p and/or chromosome 3p can differentiate between the histopathological subtypes of RCC.
Cancer Res 1992 Apr 01
PMID:Allelic losses at chromosome 17p in human renal cell carcinoma are inversely related to allelic losses at chromosome 3p. 134 14

Analyses of cancer cell lines and of anal cancers suggest an inverse correlation between infection with human papillomavirus (HPV) and somatic mutation of the p53 tumour-suppressor gene. We have investigated this association in primary cervical tumours. Tumour-tissue samples from 28 women with primary cancer of the cervix were analysed for presence of HPV sequences and for somatic mutations of the p53 gene. Southern blot analysis and the polymerase chain reaction (PCR) showed that 25 of the tumours contained HPV sequences; 20 were HPV16 positive and 5 HPV18 positive. 17 tumours subjected to restriction fragment length polymorphism analysis for the short arm of chromosome 17 showed no evidence of allelic deletion. Sequencing of the entire coding region of the p53 gene by asymmetric PCR detected heterozygous point mutations in only 3 HPV-negative tumours. By contrast, in 21 HPV-positive cancers the p53 sequence was wild-type throughout. Our data indicate that loss of wild-type p53 function is important in the pathology of cervical cancer and that in the absence of an HPV-encoded gene product that mediates loss of p53 function, somatic mutation of the gene is required. This pattern of p53 mutation may partly explain the apparently worse prognosis of HPV-negative cervical cancers.
 ...
PMID:Clonal p53 mutation in primary cervical cancer: association with human-papillomavirus-negative tumours. 135 6

Loss of genetic material on the short arm of chromosome 17 is observed in approximately 40% of human astrocytomas (WHO grades II and III) and in approximately 30% of cases of glioblastoma multiforme (WHO grade IV). Previous studies of glioblastoma multiforme have shown that the p53 gene, located on the short arm of chromosome 17, is frequently mutated in these glioblastomas. To explore whether lower-grade astrocytomas are also associated with corresponding mutations of the p53 gene, we have investigated a series of 22 human astrocytomas of WHO grades II and III both for loss of heterozygosity on chromosome 17p and for p53 mutations. Mutations in the conserved regions of the p53 gene were identified by single strand conformation polymorphism analysis of exons 5, 6, 7, and 8 and were verified by direct DNA sequencing of the polymerase chain reaction products. p53 mutations were observed in 3 of 8 grade II astrocytomas and 4 of 14 grade II astrocytomas. In all 22 tumors, allelic loss of the short arm of chromosome 17 was investigated by restriction fragment length polymorphism analysis. One-half of the grade II astrocytomas (4 of 8) and grade III astrocytomas (7 of 14) exhibited allelic loss on chromosome 17p. Mutations in the p53 gene were exclusively observed in tumors with allelic loss on 17p. Our results show that p53 mutations are not restricted to glioblastoma multiforme and may be important in the tumorigenesis of lower-grade astrocytomas and that p53 mutations in lower-grade astrocytomas are associated with loss of chromosome 17p. These findings are consistent with a recessive mechanism of action of p53 in WHO grade II and III astrocytoma tumorigenesis.
Cancer Res 1992 May 15
PMID:p53 mutations are associated with 17p allelic loss in grade II and grade III astrocytoma. 134 50

Nasopharyngeal carcinoma (NPC) is a malignancy which is consistently associated with the Epstein-Barr virus (EBV). The structure of the EBV genome in NPC suggests that NPC is a clonal proliferation of epithelial cells which emerges after EBV infection. The disease develops with high incidence in specific populations in discrete geographic locations, implicating possible genetic or environmental cofactors. Mutations of the p53 gene are among the most frequent genetic changes found in a large variety of human tumors. Mutations in p53 have been shown to abrogate the suppressor function of wild-type p53 and thus contribute to the transformed phenotype. To determine if mutation in p53 participates in the development of the malignant clone in NPC, the structure and sequence of p53 in 42 primary, metastatic, and nude mouse-passaged NPC specimens was analyzed. A high frequency (6 of 9) of mutations was detected in the nude mouse-passaged tumors, while only 2 of 15 metastatic and 0 of the 18 primary tumors harbored mutant p53. The p53 mutations included single-point mutations and more extensive changes such as frame shifts, deletion, duplication, or complete loss of coding sequences. These data indicate that alterations of the p53 gene are unlikely to be involved in the initial genetic events leading to the clonal outgrowth in NPC. However, although it is a rare NPC which can be established in nude mice, this growth advantage appears to be conferred on tumors bearing a mutant p53.
 ...
PMID:Alterations of the p53 gene in nasopharyngeal carcinoma. 134 27

K1 is a murine monoclonal antibody (MAb) derived from a hybridoma generated by the fusion of splenocytes of BALB/c mice immunized with a human ovarian tumor cell line, OVCAR-3. This antibody reacts strongly with epithelial ovarian tumors and mesotheliomas. The antigen recognized by MAb K1, designated CAK1, has recently been characterized as a 40-kDa protein probably anchored to the cell surface by glycosyl-phosphatidylinositol. Using immunoperoxidase histochemical methods, we examined 37 squamous-cell carcinoma (SqCC) samples from cervix, lung, esophagus and other origins, and 12 normal squamous epithelia of the cervix and esophagus for their reactivity with MAb K1. Of the SqCC specimens, 81% showed K1 reactivity with variable intensity, but none of 12 normal tissue samples of squamous epithelia did so. Two patterns of CAK1 expression in tumor samples were found, i.e., a heterogeneous pattern with strong intensity, and a homogeneous pattern with weak intensity. Three carcinomas in situ of the larynx, vulva and esophagus were moderately positive with K1, suggesting that CAK1 antigen may occur in the early stage of carcinogenesis of SqCC. The expression of CAK1 was also compared with expression of CA125, HER-2/neu, p53 and P-glycoprotein, and MAb K1 was found to react most consistently with SqCC. Since K1 reacts with a majority of cervical and esophageal carcinomas but has no detectable reactivity in normal epithelia of the cervix uteri and esophagus, MAb K1 could be of value as a reagent to help distinguish between normal and neoplastic cells on sections as well as in cytological samples.
Int J Cancer 1992 Jun 19
PMID:Frequent expression of the tumor antigen CAK1 in squamous-cell carcinomas. 135 Oct 45

Mutation of the p53 tumor suppressor gene is a recurring event in a variety of human cancers. Wild-type p53 may regulate cell proliferation and has recently been shown to repress transcription from several cellular promoters. We studied the effects of wild-type and mutant human p53 on the human proliferating-cell nuclear antigen promoter and on several viral promoters including the simian virus 40 early promoter-enhancer, the herpes simplex virus type 1 thymidine kinase and UL9 promoters, the human cytomegalovirus major immediate-early promoter-enhancer, and the long terminal repeat promoters of Rous sarcoma virus, human immunodeficiency virus type 1, and human T-cell lymphotropic virus type I. HeLa cells were cotransfected with a wild-type or mutant p53 expression vector and plasmids containing a chloramphenicol acetyltransferase reporter gene under viral (or cellular) promoter control. Expression of wild-type p53 correlated with a consistent and significant (6- to 76-fold) reduction of reporter enzyme activity. A mutation at amino acid 143 of p53 releases this inhibition significantly with all the promoters studied. Expression of a p53 mutated at any one of the five amino acid positions 143, 175, 248, 273, and 281 also correlated with a much smaller (one- to sixfold) reduction of reporter enzyme activity from the herpes simplex virus type 1 thymidine kinase promoter. These mutant forms of p53 are found in various cancer cells. Thus, failure of tumor suppression correlates with loss of the promoter inhibitory effect of p53.
 ...
PMID:Inhibition of viral and cellular promoters by human wild-type p53. 135 31


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>