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)

Some oral cancers are preceded by premalignant lesions which include leucoplakia and erythroplakia. At present there are no reliable markers to identify lesions that may progress to malignancy. We have analysed 30 potentially malignant oral lesions for deletions at chromosomal regions that harbour tumour-suppressor genes for oral cancer. A total of 16 of 30 cases (53%) showed loss of heterozygosity (LOH) or allele imbalance at TP53, DCC, 3p21.3-22.1 or 3p12.1-13. These genetic alterations were detected in dysplastic lesions but not in histologically normal mucosa and may be early events in the carcinogenic process. A total of 64% of dysplastic lesions that recurred during the study showed LOH or allele imbalance in the initial biopsy and the number of genetic abnormalities increased in the tumours that developed. This type of molecular profiling may help to identify patients with lesions that may recur or acquire additional genetic events and progress to malignancy.
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PMID:Frequent gene deletions in potentially malignant oral lesions. 861 86

HPV-immortalized human oral keratinocytes can convert to tumorigenic cells when exposed to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), but normal human oral keratinocytes cannot transform with a similar exposure. The different responses of these cells could be due to different genetic stability of cells. In as much as genetic stability is determined by cell cycle control and of repair of damaged DNA, we studied the effect of MNNG exposure upon cell cycle progression, expression of p53, WAF1/CIP1 and gadd45, and the mutation frequency of a shuttle vector pS189 in normal human oral keratinocytes, in HPV-immortalized oral keratinocytes, and in an oral cancer cell line expressing mutant p53. Normal cells demonstrated transient cell cycle arrest after exposure to MNNG, but the other tested cells did not. While MNNG exposure significantly increased the levels of intranuclear wt p53 protein and the expression of WAF1/CIP1 and gadd45 genes in normal cells, it did not alter them in the immortalized and cancer cells. The mutation frequency of pS189 plasmid was significantly lower in normal cells than in the other tested cells. These data indicate that malignant conversion of HPV-immortalized oral keratinocytes may, in part, be associated with the cells' genetic instability. The genetic instability may be due to cells' (1) inability to accumulate intranuclear wt p53 to a threshold level at which p53 upregulates the transcription of WAF1/CIP1 and gadd45, resulting in the loss of cell cycle control and (2) inefficient repair of DNA damage caused by genotoxic agents.
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PMID:Oncogenic transformation of HPV-immortalized human oral keratinocytes is associated with the genetic instability of cells. 864 1

The incidence of squamous cell carcinoma in patients with oral submucous fibrosis (OSF) exceeds 7 per cent. The proliferative cell nuclear antigen (PCNA) is a convenient marker of epithelial cell proliferation and p53 tumour suppressor gene mutations or deletions are frequent in oral cancer. The present study estimated the basal epithelial cell growth fraction using a standard immunohistological method for the detection of nuclear PCNA from 20 Nepalese patients with OSF as 31.8 per cent compared with 7.6 per cent for oral mucosa from 43 normal subjects (p < 0.001) and 39.4 per cent for 44 patients with oral cancer. The PCNA growth fraction correlated significantly with that derived by Ki-67 labelling. There was no correlation between the growth fraction and the severity of epithelial dysplasia found is OSF. Abnormal expression of p53 protein identified by immunohistochemistry with a panel of antibodies was found in 70 per cent of the OSF specimens, and 21 per cent of mucosal specimens from subjects with clinically normal mouths. PCNA-positive cells and p53 expression were restricted to the basal epithelial layer in OSF. The unexpected finding of p53 protein in clinically healthy mucosa was confined to subjects aged over 40 years who smoked tobacco, a known risk factor for oral cancer. There was no association between p53 expression and epithelial atypia scores in OSF. It is concluded that the proportion of actively cycling epithelial cells is increased in OSF and that p53 tumour suppressor gene mutations or deletions may be prevalent. Confirmation by molecular biology techniques of this genetic damage is now needed.
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PMID:Epithelial growth fraction and expression of p53 tumour suppressor gene in oral submucous fibrosis. 867 41

With the ultimate goal of characterizing the molecular pathogenesis of oral cancer, the most predominant malignancy in India, immunocytochemical evaluation of p53 and bcl-2 proteins was carried out in hypeplastic oral mucosa, dysplastic oral mucosa and invasive oral cancer. All subjects gave a similar and almost uniform history of prolonged use of betal quid and tobacco. Expression of p53 was insignificant while bcl-2 was absent in hyperplastic leukoplakia lesions. Both proteins were however expressed in leukoplakia with apparent dysplasia. Almost all invasive cancer lesions showed high levels of both p53 and bcl-2. Good correlation was therefore evident between expression of these two proteins and increasing histologic abnormality. Moreover relative risk evaluation revealed that lesions expressing p53 and bcl-2 had a high probability of having a histology of dysplasia or worse. Since it has been previously shown that wild type p53 regulates the expression of bcl-2, it may be presumed that the protein detected in the dysplastic and malignant oral tissue is of the mutant type. It is also known that p53 is a positive regulator of programmed cell death or apoptosis while bcl-2 is an anti-apoptotic protein. This suggests the possibility that alterations in p53 followed by over-expression of bcl-2 occur early in oral carcinogenesis resulting in defective apoptosis and subsequent tumor progression.
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PMID:Expression of programmed cell death regulatory p53 and bcl-2 proteins in oral lesions. 869 36

Oral cancer, although uncommon in the Western world, accounts for up to 40% of all malignancies in parts of India and South East Asia. Recognised aetiological agents of oral cancer include tobacco and alcohol. This paper reviews the spectrum of molecular changes found in oral squamous cell carcinomas from Western (U.K., U.S.A., Australia) and Eastern (India, S.E. Asia) countries. p53 mutations are common in tumours from the West (47%) but are infrequent in the East (7%). Tumours from India and South East Asia are characterised by the involvement of ras oncogenes, including mutation, loss of heterozygosity (H-ras) and amplification (K- and N-ras), events which are uncommon in the West. The possibility that these genetic differences reflect aetiology and/or ethnic origin is discussed.
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PMID:Molecular changes in oral cancer may reflect aetiology and ethnic origin. 876 70

Many human cervical and oral carcinomas express RNA of human papillomaviruses, and the RNA transcript provides a potential target for gene therapy of these carcinomas. Three hammerhead ribozymes that were targeted to RNA of human papillomavirus type 18 (HPV-18) were cloned into a plasmid expression vector. Each plasmid was then transfected into the HPV-18-expressing cell line. HeLa, or the non-HPV-expressing oral cancer cell line, Tu167. None of the ribozymes had any effect on the phenotype of Tu167 cells. In contrast, each ribozyme affected the phenotype of HeLa cells, causing reduced growth rates, increased serum dependency, and reduced focus formation in soft agar. A molecule that had the same antisense sequences as a ribozyme but lacked the catalytic sequences affected the HeLa cell phenotype to a much lesser extent. The effects of two of the ribozymes could be attributed in part to an increased intracellular concentration of the tumor suppressor protein p53. The most effective ribozyme was targeted to nucleotide 309 in the HPV-18 transcript, but each of the three ribozymes appears to have potential for gene therapy of cancers that express HPV-18.
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PMID:Effects on tumor cells of ribozymes that cleave the RNA transcripts of human papillomavirus type 18. 878 6

India has one of the world's highest incidences of oral cancer. It is believed that the widespread habit of betel quid chewing is an important risk factor as it exposes the oral mucosa to known carcinogens. It also induces physical abrasions, which may create mitogenic environments during wound healing as gateways for infections. A recent study from our laboratories identified human papillomavirus (HPV) DNA, mostly of the high-risk types HPV-16 and HPV-18, in 67 of 91 oral cancer lesions from a cohort of Indian patients consisting mostly of betel quid users. This suggested a viral etiology of some lesions but tumorigenesis in the absence of viruses in other lesions. Here, we examined whether the p53 gene, whose function is abrogated by the product of the HPV gene E6, would be mutated in those oral cancers that were free of HPV DNA, and we found point mutations at known hot spots for mutational alteration of p53 in 4 of 23 lesions. We also considered the possibility that p21, a target of regulation by the p53 protein, may be mutationally altered in tumors with a functional p53 gene. While we did not identify mutations in the p21 gene, 6 of 11 lesions contained a polymorphism that may be associated with cancer. Interestingly, 3 of 23 lesions had mutations in the p16 gene, a third regulator of the cell cycle which is frequently mutated in melanoma but rarely in other cancers, with 1 lesion even having a mutation in the p53 as well as in the p16 gene. Our data point to p53 and p16 as gene targets of oral carcinogenesis, with chemicals in the betel quid possibly functioning in these tumors as carcinogens.
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PMID:Mutations and polymorphisms in the p53, p21 and p16 genes in oral carcinomas of Indian betel quid chewers. 894 9

Oral submucous fibrosis (OSF) affects an estimated 2.5 million people, mostly in the Indian subcontinent. Limitation of oral opening resulting in difficulty in eating is the main presenting feature. Although nutritional deficiencies and immunological processes may play a part in the pathogenesis, the available epidemiological evidence indicates that chewing betel quid (containing areca nut, tobacco, slaked lime or other species) is an important risk factor for OSF. Genetically determined susceptibility could explain why only a small fraction of those using betel quid develop the disease. In OSF there is an incidence of oral cancer of 7.6 per cent for a median 10-year follow-up period. Risk markers for malignant transformation in OSF include epithelial dysplasia, silver binding nucleolar organizer region counts, and sister-chromatid exchange frequencies; p53 tumour suppressor gene mutations may be involved in these potentially malignant changes.
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PMID:Oral submucous fibrosis. A review. 896 1

Recent reports of p53 positivity in the normal mucosa of some head and neck cancer patients have been taken as evidence for field cancerization and hence a likelihood of the development of further tumours, yet few papers report the clinical significance of this finding through long-term follow-up. The immunohistochemical detection of p53 expression in clinically and histopathologically normal oral mucosa taken from the wound margin following excision of oral cancer was assessed using the polyclonal antibody CM1. Fresh frozen biopsies of normal oral mucosa and the corresponding tumour from 21 oral cancer patients and of normal mucosa from 25 non-cancer patients were assessed for p53 overexpression. The 'normal' mucosa was positive in 12 of the oral cancer patients and one of the non-cancer patients. Second malignant tumours were seen in patients from whom p53-positive 'normals' and p53-negative 'normals' were recorded. In five of the p53-positive 'normals', the corresponding cancer was p53-negative. In one case, where 'normal' mucosa was available from more than one site, one region was positive, whilst the other was negative. No obvious difference in age, tobacco use, or recurrence rate was seen between positive and negative cases. All patients who were still alive were reviewed for a minimum of 5 years. Using Fisher's exact test, no statistically significant difference was found for the rate of second malignant tumours occurring in patients with p53-positive compared with p53-negative normal mucosa. Thus, the detection of p53 in normal mucosa did not necessarily predict a further tumour.
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PMID:Overexpression of p53 in normal oral mucosa of oral cancer patients does not necessarily predict further malignant disease. 927 28

The CDKN2A gene encodes p16 (CDKN2A), a cell-cycle inhibitor protein which prevents inappropriate cell cycling and, hence, proliferation. Germ-line mutations in CDKN2A predispose to the familial atypical multiple-mole melanoma (FAMMM) syndrome but also have been seen in rare families in which only 1 or 2 individuals are affected by cutaneous malignant melanoma (CMM). We therefore sequenced exons 1alpha and 2 of CDKN2A using lymphocyte DNA isolated from index cases from 67 families with cancers at multiple sites, where the patterns of cancer did not resemble those attributable to known genes such as hMLH1, hMLH2, BRCA1, BRCA2, TP53 or other cancer susceptibility genes. We found one mutation, a mis-sense mutation resulting in a methionine to isoleucine change at codon 53 (M531) of exon 2. The individual tested had developed 2 CMMs but had no dysplastic nevi and lacked a family history of dysplastic nevi or CMM. Other family members had been diagnosed with oral cancer (2 persons), bladder cancer (1 person) and possibly gall-bladder cancer. While this mutation has been reported in Australian and North American melanoma kindreds, we did not observe it in 618 chromosomes from Scottish and Canadian controls. Functional studies revealed that the CDKN2A variant carrying the M531 change was unable to bind effectively to CDK4, showing that this mutation is of pathological significance. Our results have confirmed that CDKN2A mutations are not limited to FAMMM kindreds but also demonstrate that multi-site cancer families without melanoma are very unlikely to contain CDKN2A mutations.
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PMID:CDKN2A mutation in a non-FAMMM kindred with cancers at multiple sites results in a functionally abnormal protein. 938 68


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