Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our understanding of the molecular pathology underlying the development and progression of ductal pancreatic cancer has been revolutionised during the last 5 years due to the spectacular development of novel molecular biological techniques. In the present article, we describe key molecular alterations of sporadic and inherited ductal pancreatic cancer. Overexpression of growth factors and growth factor receptors are present in a significant proportion of this tumour type. Mutation of the K-ras oncogene, and disruption of p53 or p16 tumour suppressor gene abrogates the control of the cyclin-dependent kinases (cdk) and retinoblastoma (Rb) gene pathway, causing continuous growth of the pancreatic tumour. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor beta signalling pathway. Lost or decreased expression of retinoid receptors and failure of telomerase activity may play a role in pancreatic carcinogenesis. Tumour-associated proteinases, matrix metalloproteinases and plasminogen activators are reported to be involved in pancreatic cancer invasion and metastasis. Furthermore, the cytogenetic changes in this cancer are summarised. This molecular pattern distinguishes pancreatic cancer from other epithelial tumours and represents a promising basis for the development of diagnostic and other clinical applications.
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PMID:Molecular pattern of ductal pancreatic cancer. 964 82

Loss of DNA mismatch repair has been described in a number of tumour types such as colorectal adenocarcinoma and leads to microsatellite instability. This may have clinical relevance due to mismatch repair defects altering chemosensitivity towards certain classes of anti-tumour agent. This study has examined microsatellite instability of eight murine colon adenocarcinoma tumour models induced by 1,2-dimethylhydrazine. Four microsatellite regions were examined suggesting that four of the tumour models exhibit a low level of microsatellite instability. Loss of heterozygosity was found in 5/8 tumours, suggesting that allelic loss may be a relatively common step in the carcinogenesis of these tumour models. Three of the allelic losses involved the D11MIT4 locus which is situated very close to the p53 tumour suppressor locus. Four tumour models are routinely cultured in vitro and these were used to examine whether there was any association between microsatellite instability, mutant frequency and chemo-sensitivity of these tumour models, comparing them with four human adenocarcinoma cell lines of known mismatch repair status. Two cell lines (MAC26 and MAC16) were found to be more chemoresistant towards cisplatin but not 6-thioguanine. No association was found between microsatellite instability and chemosensitivity for either the human or mouse cell lines.
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PMID:Microsatellite instability, chemosensitivity and mutant frequency in a series of 1,2-dimethylhydrazine induced murine colon adenocarcinoma models. 968 89

The p53 tumour suppressor gene is frequently mutated in oral squamous cell carcinomas. However, the downstream mechanism of p53 during oral carcinogenesis is not fully understood. The cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21), which can be induced by wild-type p53, functions as a downstream mediator of the antiproliferative and apoptosis-inducing actions of wild-type p53. To learn more about the roles of the p53 gene and its downstream mechanism, we evaluated p53 gene mutation and immunohistochemical expression of p53 and p21 in 20 cases of oral squamous cell carcinoma. p53 gene mutations were observed in 7 cases (35%). Overexpression of p53 was found in 4 of 13 cases with wild-type p53, and in 6 of 7 cases with p53 mutations. p21 expression was detected in 15 of 20 cases (75%). The expression of p21 correlated neither with mutated p53 mutation nor with p53 protein overexpression. p21 was expressed even in carcinomas in which molecular analysis revealed a nonsense mutation. In normal oral mucosa, p21 expression was limited in the differentiating spinous cell layer. However, dysplastic or hyperplastic epithelium adjacent to the tumour demonstrated the increased expression of p21 even in the proliferating basal cell layer. These molecular and immunohistochemical data did not show any correlation with various clinico-pathologic parameters. These results suggest that p53 gene mutations and altered expression of p21 are commonly involved in oral carcinogenesis, but do not correlate with each other or with the clinico-pathologic parameters. They also suggest that p21 expression in oral squamous cell carcinomas may be induced by a p53-independent pathway.
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PMID:Expression of p21WAF1/CIP1 is unrelated to p53 tumour suppressor gene status in oral squamous cell carcinomas. 969 54

Oral cancer is a disease of the elderly and is closely connected with cigarette smoking and alcohol consumption. Since the successful introduction of multidisciplinary treatment, the survival rate has not changed. Because of the high mortality and potentially disfiguring treatment, today's efforts are aimed at eliminating risk factors, chemoprophylaxis, improvement in diagnostic procedures, and understanding of the genetic mechanisms of oral carcinogenesis. Immunohistochemical and molecular biology analysis of biopsy tissue and cell lines of preneoplastic and neoplastic lesions that originate from the oral mucosa have shown that alterations in tumour suppressor genes such as p53 and Rb gene may have an important role in oral carcinogenesis and may be potentially useful prognostic 'biomarkers' in oral carcinogenesis. Statistical analysis of immunohistochemical data from 216 patients did not identify significant or consistent differences of p53, MDM2, or RB expression with respect to stage of disease, malignant transformation, metastatic node involvement, recurrence, or survival. Nevertheless, p53 overexpression seems to correlate strongly with histological progression of the disease, which confirms the importance of p53 alterations in oral carcinogenesis. Overexpression of p53 is usually found in the less differentiated proliferating cells in benign and malignant oral lesions. Assessment of the proliferating activity is possible by immunohistochemical staining with monoclonal antibodies against proliferating nuclear antigen and Ki-67. Statistical analysis shows that overexpression of p53 combined with high proliferative activity predicts a less favourable course of disease in oral squamous cell carcinoma.
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PMID:Proliferative activity and loss of function of tumour suppressor genes as 'biomarkers' in diagnosis and prognosis of benign and preneoplastic oral lesions and oral squamous cell carcinoma. 976 52

The p53 tumour suppressor gene has an important role in the the maintenance of genome stability and its mutational inactivation may be at the origin of aneuploidy in cancer cells. The aim of this study was to determine whether p53 mutations were associated to DNA aneuploidy, as assessed by flow cytometry, in colorectal adenocarcinomas. Analysis of p53 mutations spectrum of the sorted nuclei was done by Denaturing Gradient Gel Electrophoresis (DGGE) and DNA sequencing. Overall, we studied 20 adenocarcinomas, the corresponding control mucosa, and 7 lymph node metastases. Five tumours (25%) were DNA diploid, while 15 tumours (75%) were composed of DNA aneuploid and diploid subpopulations. DNA diploid control mucosa and adenocarcinomas showed no p53 mutations, while 60% of the tumours with DNA aneuploidy had p53 mutations. Therefore, p53 mutations occurred significantly more often in DNA aneuploid than in DNA diploid tumours (p < 0.04, Fisher's exact test). Incidences of DNA aneuploidy and p53 mutations in lymph node metastases were 60 and 86%, respectively. In all tumours showing a p53 mutation, the wild-type allele was not or only bearly visible in DNA aneuploid cells suggesting that, in such cells, aneuploidy is accompanied by complete p53 functional inactivation. The present observations suggest that p53 mutations may have a role in the origin of aneuploidy at late stages of colorectal carcinogenesis.
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PMID:p53 mutations and DNA ploidy in colorectal adenocarcinomas. 980 34

The different proteins of the E-cadherin/catenin cell-cell adhesion complex are believed to play a predominant role in carcinogenesis. Aberrant expression of these proteins has been found in many different human carcinomas, indicating abnormal regulation. In general, inactivating mutations of the human E-cadherin gene are rare; they are, however, highly frequent in infiltrating lobular breast carcinomas and in diffuse gastric carcinomas. These mutations mostly occur in combination with loss of heterozygosity (LOH) of the wild-type allele. Mutations were found at very early non-invasive stages, thus associating E-cadherin mutations with loss of growth control and defining E-cadherin as a real tumour suppressor for these particular tumour types. Defects affecting both alleles of the alpha E-catenin gene have been found in different human carcinoma cell lines, resulting in the loss of E-cadherin-mediated cell-cell adhesion. Mutations of the beta-catenin gene in colon tumours and melanomas were found to result in an accumulation of the protein in the cytosol. Upon translocation to the nucleus, this beta-catenin enhances TCF/LEF-dependent transcriptional activity. This suggests that mutated beta-catenin can act as an oncogene in these particular tumour types. The multiple interaction partners of beta-catenin are known to be involved in signal transduction, actin organization, protein phosphorylation or transcriptional regulation. This makes this protein an intriguing alternative target for either activation or inactivation in human cancer types characterized by frequent E-cadherin or APC deficiencies.
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PMID:Dysregulation of the E-cadherin/catenin complex by irreversible mutations in human carcinomas. 982 69

The p53 tumour suppressor protein can be rendered ineffective by mutations in the p53 gene or by interactions with proteins of DNA-transforming viruses, including Human Papillomaviruses (HPVs). Our aim was to determine whether the inactivation of p53, caused by a mutation of gene itself or by HPV is involved in anogenital carcinogenesis. We studied p53 overexpression by immunohistochemical methods, and HPV/DNA by non isotopic in situ hybridization method in 137 anogenital lesions. Immunoreactivity for p53 was seen in 5% of condylomata acuminata, in 12% of low-grade CINs, in 3.5% of high-grade CINs, and in 17% of invasive cervical carcinomas. Two (67%) of three condylomata acuminate p53+ harboured HPV/DNA. The concomitant presence of p53 and HPV was not detected in intraepithelial and invasive cervical lesions. Our findings suggest that p53 inactivation does not seem to play an important role in anogenital carcinogenesis. Further investigation of the concomitant presence of p53 and HPV in condylomata acuminate and its role in recurrences or progression of these lesions is needed.
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PMID:Immunohistochemical detection of p53 protein in anogenital lesions and its relationship with HPV status. 989 51

The gene mutated in ataxia telangiectasia (ATM) has an established tumour suppressor role in breast cancer. ATM appears to be expressed in most normal cells, including breast epithelium, where it has been postulated to have a nuclear role in cell cycle regulation following DNA damage. However, ATM is not upregulated after DNA damage. In this study, we demonstrate an absence of immunohistologically detectable levels of ATM in the normally quiescent myoepithelial cells that line normal breast ducts. This contrasts dramatically with the significant expression of ATM in the proliferative myoepithelium of sclerosing adenosis (n = 7). This upregulation of ATM suggests that ATM expression is coupled to the proliferative status of the myoepithelium. Our results also indicate that there are factors other than ATM gene mutations that can dramatically influence ATM expression in the breast and that these factors should be considered for their possible implications in carcinogenesis.
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PMID:Upregulation of ATM in sclerosing adenosis of the breast. 989 51

The activation of oncogenes and the inactivation of tumour suppressor genes play a critical role in laryngeal tumorigenesis. Recent investigations revealed that 8p, 9p and 17q arms of human chromosomes harbour tumour suppressor genes (TSGs) such as p16 and BRCA1 with an important role in the multistage carcinogenesis of the larynx. In order to investigate the implication of these novel TSGs in the development of laryngeal neoplasia we performed a loss of heterozygosity (LOH) analysis using a bank of 15 polymorphic microsatellite markers (4 at 8p21, 7 at 9p21 arm and 4 at 17q arm surrounding the BRCA1 region) in a series of 32 cytological specimens (19 squamous cell carcinoma, 13 benign lesions of the larynx). Both benign and malignant specimens exhibited genetic alterations with at least one microsatellite marker. Fifteen (47%) out of the 32 specimens exhibited LOH at 8p21, 25/32 (78%) showed LOH at 9p21 and 18/32 (56%) displayed LOH at 17q21. Genetic alterations were detected in both benign and malignant lesions for all the loci tested suggesting an important role of these regions in the development of laryngeal neoplasia. This is the first report of detection of microsatellite alterations not only in solid tumours of the larynx but in laryngeal cytological specimens, suggesting that microsatellite analysis may be a useful tool in the primary diagnosis of the disease.
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PMID:Loss of heterozygosity at 8p, 9p and 17q in laryngeal cytological specimens. 993 Mar 65

Evidence from both experimental carcinogenesis and studies in human cirrhotic liver suggest that defective repair of the promutagenic DNA base lesion, O6-methylguanine, is a factor in the multistep process of hepatocellular carcinogenesis. Ubiquitous environmental alkylating agents such as N-nitroso compounds can produce O6-methylguanine in cellular DNA. Unrepaired, O6-methylguanine can lead to the formation of G --> A transition mutations, a known mechanism of human oncogene activation and tumour suppressor gene inactivation. Combined treatment of rodents with an agent producing O6-methylguanine in DNA, and an agent promoting cell proliferation, leads to development of hepatic nodules and hepatocellular carcinoma (HCC), cell division, hence DNA replication, being required for the propagation of tumorigenic mutation(s) in hepatocyte DNA. The paramount importance of O6-methylguanine in hepatocellular carcinogenesis is indicated by the observation that transgenic mice engineered to have increased hepatic levels of repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) are significantly less prone to hepatocellular carcinogenesis following alkylating agent treatment. Cirrhosis is a universal risk factor for development of human HCC, and a condition that is characterized by increased hepatocyte proliferation as a result of tissue regeneration. Levels of the human repairing enzyme for O6-methylguanine were found to be significantly lower in cirrhotic liver than in normal tissue. In accord with findings from animal models, this suggested a mechanism in which persistence of O6-methylguanine due to defective DNA repair by MGMT, together with increased hepatocyte proliferation, might lead to specific gene mutation(s) and hepatocellular carcinogenesis. Screening for the presence and persistence of O6-methylguanine in human DNA presently involves formidable technical difficulty. Indications are that such limitations might be overcome by the use of an ultrasensitive method such as immuno-polymerase chain reaction (PCR). This approach should allow parallel measurement of DNA adduct and repair enzyme in routine liver biopsy samples. It might also enable investigation of O6-methylguanine in human genes specifically associated with hepatocellular carcinogenesis. Given the wide variation in human MGMT levels observed between individuals, tissues, and cells, this technology should be adapted to permit the ultrasensitive localisation and measurement of adducts and repairing enzyme in liver biopsy tissue sections. Ability to ultrasensitively measure O6-methylguanine, and its repair enzyme, should prove valuable in the risk assessment of cirrhotic patients for developing hepatocellular carcinoma.
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PMID:Repair of DNA lesion O6-methylguanine in hepatocellular carcinogenesis. 993 84


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