UNIPROT:P43146 - FACTA Search

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)

The mechanism by which germline mutations of DNA mismatch repair genes cause susceptibility to tumour formation is not yet understood. Studies in vitro indicate that heterozygosity for these mutations, unlike homozygosity, does not affect mismatch repair. Surprisingly, no loss of heterozygosity at the predisposing loci has so far been described in hereditary nonpolyposis colorectal cancers. Here, we show that loss of heterozygosity (LOH) of markers within or adjacent to the MLH1 gene on chromosome 3p occurs nonrandomly in tumours from members of families in which the disease phenotype cosegregates with MLH1. In every informative case, the loss affects the wild type allele. These results suggest that DNA mismatch repair genes resemble tumour suppressor genes in that two hits are required to cause a phenotypic effect.
...
PMID:Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. 789 94

The majority of hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in DNA mismatch repair genes, especially in MLH1 and MSH2. Tumours in such patients also show microsatellite instability characteristic for DNA repair defects. The FHIT gene, a candidate tumour suppressor gene located at 3p14.2 has been shown to be involved in carcinogenesis of many human tissues, including digestive tract tissues. In our study, we characterized Fhit protein expression in hereditary and sporadic colorectal cancers (CRC). Our intention was to determine if cancers with mutations in the mismatch repair genes, MSH2 and MLH1, would show more frequent inactivation of the FHIT gene. Sixteen HNPCC and 28 sporadic CRC cases were examined by standard immunohistochemical analyses. Both study groups comprised carefully and selectively chosen cases. We have observed higher frequency of loss or reduction of Fhit protein expression in hereditary CRC than in sporadic cases (44% vs. 25%). Although this difference was not statistically significant (p = 0.17), possibly due to the small number of available tumour specimens, the tendency is interesting. More extensive studies on a larger number of cases should be done in the HNPCC group to confirm statistical significance. Our results suggest that the FHIT gene plays an important role in carcinogenesis of at least one fourth of all colorectal cancers.
...
PMID:Fhit protein expression in hereditary and sporadic colorectal cancers. 1176 99

Histone deacetylation and DNA methylation have a central role in the control of gene expression, including transcriptional repression of tumour suppressor genes. Loss of DNA mismatch repair due to methylation of the hMLH1 gene promoter results in resistance to cisplatin in vitro and in vivo. The cisplatin-resistant cell line A2780/cp70 is 8-fold more resistant to cisplatin than the non-resistant cell line, and has the hMLH1 gene methylated. Treatment with an inhibitor of DNA methyltransferase, DAC (2-deoxy-5'-azacytidine), results in a partial reversal of DNA methylation, re-expression of MLH1 (mutL homologue 1) and sensitization to cisplatin both in vitro and in vivo. PXD101 is a novel hydroxamate type histone deacetylase inhibitor that shows antitumour activity in vivo and is currently in phase I clinical evaluation. Treatment of A2780/cp70 tumour-bearing mice with DAC followed by PXD101 results in a marked increase in the number of cells that re-express MLH1. Since the clinical use of DAC may be limited by toxicity and eventual re-methylation of genes, we suggest that the combination of DAC and PXD101 could have a role in increasing the efficacy of chemotherapy in patients with tumours that lack MLH1 expression due to hMLH1 gene promoter methylation.
...
PMID:Epigenetic approaches to cancer therapy. 1550 76

The CpG-island methylator phenotype (CIMP+) in colorectal cancer (CRC) is characterised by frequent hypermethylation of promoter regions in tumour suppressor genes. Low level methylation of some CpG islands is also seen in the normal colonic mucosa and increases with age; however, it is still unclear what other factors regulate this phenomenon. The first aim of our study was to determine whether the level of promoter methylation is elevated in the normal colonic mucosa of patients with CIMP+ tumours. The second aim was to investigate whether common, functional polymorphisms in genes involved in methyl group metabolism are associated with the level of methylation in this tissue. CpG islands within the ERalpha, MYOD, P16(INK4A), MLH1, APC, P14(ARF), DAPK and TIMP3 genes were quantitatively evaluated for methylation in normal colonic mucosa from a large series of CRC patients using the MethyLight assay. Genotyping was carried out for polymorphisms in the MTHFR, TS, MS, MTHFD1 and DNMT3b genes. Methylation of ERalpha and MYOD in normal colonic mucosa increased with age and was higher in female subjects. Methylation of P16(INK4A), MLH1, TIMP3 and DAPK in normal mucosa occurred at a lower level than ERalpha and MYOD but also increased with age and was significantly higher in patients with CIMP+ tumours. The DNMT3b C46359T polymorphism was associated with significantly less methylation of MYOD and MLH1 and with trends for lower methylation in each of the other CpG islands examined. Our results demonstrate that age, gender and genetic factors can influence the methylation level of CpG islands in gene promoter regions of normal colonic mucosa. Further work is required to determine whether such methylation is associated with the development of CIMP+ CRC.
...
PMID:DNA hypermethylation in the normal colonic mucosa of patients with colorectal cancer. 1642 93

Alternative splicing produces more than one protein from the majority of genes and the rarer forms can have dominant functions. Instability of alternative transcripts can also hinder the study of regulation of gene expression by alternative splicing. To investigate the true extent of alternative splicing we have developed a simple method of enriching alternatively spliced isoforms (EASI) from PCRs using beads charged with Thermus aquaticus single-stranded DNA-binding protein (T.Aq ssb). This directly purifies the single-stranded regions of heteroduplexes between alternative splices formed in the PCR, enabling direct sequencing of all the rare alternative splice forms of any gene. As a proof of principle the alternative transcripts of three tumour suppressor genes, TP53, MLH1 and MSH2, were isolated from testis cDNA. These contain missing exons, cryptic splice sites or include completely novel exons. EASI beads are stable for months in the fridge and can be easily combined with standard protocols to speed the cloning of novel transcripts.
...
PMID:EASI--enrichment of alternatively spliced isoforms. 1695 Dec 90

p53 and the prostate-cancer-susceptibility gene RNASEL are tumour suppressor genes involved in apoptosis. We have previously reported that the common, functionally different variants Arg72Pro in p53 and Arg462Gln in RNASEL are associated with the age of disease onset of colorectal cancer in Lynch syndrome patients. To assess the combined effect of both variants, we screened 246 unrelated Lynch syndrome patients with a pathogenic germline mutation either in MSH2 (n=138) or in MLH1 (n=108) and colorectal cancer as first tumour, and 245 healthy controls. The global log rank test revealed significant differences in the age of disease onset for the genotypes of each variant (p=0.0176 for p53 and p=0.0358 for RNASEL) and for the combined genotypes of both variants (p=0.0174). The highest difference in median age of disease onset was seen between homozygotes for the wild-types in both genes (42years [range 22-75]) and homozygotes for the variant alleles in both genes (30years [range 26-47]). A multivariate Cox regression model indicated that only the p53 and RNASEL genotypes had a significant influence on age of disease onset (p=0.016 for p53 and p=0.014 for RNASEL) in an additive mode of inheritance, and that the effects of both variants are purely additive, which supports the notion that the p53 and RNaseL pathways do not interact. These findings may be relevant for preventive strategies in Lynch syndrome.
...
PMID:The additive effect of p53 Arg72Pro and RNASEL Arg462Gln genotypes on age of disease onset in Lynch syndrome patients with pathogenic germline mutations in MSH2 or MLH1. 1722 35

Histone deacetylation and DNA methylation have a central role in the control of gene expression in tumours, including transcriptional repression of tumour suppressor genes and genes involved in sensitivity to chemotherapy. Treatment of cisplatin-resistant cell lines with an inhibitor of DNA methyltransferases, 2-deoxy-5'azacytidine (decitabine), results in partial reversal of DNA methylation, re-expression of epigenetically silenced genes including hMLH1 and sensitisation to cisplatin both in vitro and in vivo. We have investigated whether the combination of decitabine and a clinically relevant inhibitor of histone deacetylase activity (belinostat, PXD101) can further increase the re-expression of genes epigenetically silenced by DNA methylation and enhance chemo-sensitisation in vivo at well-tolerated doses. The cisplatin-resistant human ovarian cell line A2780/cp70 has the hMLH1 gene methylated and is resistant to cisplatin both in vitro and when grown as a xenograft in mice. Treatment of A2780/cp70 with decitabine and belinostat results in a marked increase in expression of epigenetically silenced MLH1 and MAGE-A1 both in vitro and in vivo when compared with decitabine alone. The combination greatly enhanced the effects of decitabine alone on the cisplatin sensitivity of xenografts. As the dose of decitabine that can be given to patients and hence the maximum pharmacodynamic effect as a demethylating agent is limited by toxicity and eventual re-methylation of genes, we suggest that the combination of decitabine and belinostat could have a role in the efficacy of chemotherapy in tumours that have acquired drug resistance due to DNA methylation and gene silencing.
...
PMID:Combined inhibition of DNA methylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo. 1925 94

Mutations in the tumour suppressor HRPT2 occur in patients with parathyroid carcinoma, kidney tumours and Hyperparathyroidism-Jaw Tumour syndrome. Disruption of exonic splicing through mutation of donor/acceptor splice sites or exonic splice enhancer (ESE) sites leads to loss of function of a number of major tumour suppressors including BRCA1, APC and MLH1. Given that the effect of HRPT2 mutations on splicing has not been widely studied, we used an in vitro splicing assay to determine whether 17 HRPT2 mutations located in hot-spot and other exons predicted to disrupt ESE consensus sites led to aberrant splicing. Using two independent web-based prediction programs, the majority of these mutations were predicted to disrupt ESE consensus sites; however, aberrant splicing of HRPT2 transcripts was not observed. Canonical donor or acceptor splice site mutations were also investigated using this splicing assay and transcripts assessed from tumour tissue. Splice site mutations were shown to lead to either exon skipping or retention of intronic sequences through the use of cryptic splice sites comprised of non-classical splicing signals. Aberrant splicing caused by disruption of ESE sites does not appear to have a major role in HRPT2-associated disease; however, premature truncation of parafibromin as the result of canonical donor or acceptor splice site mutations is associated with pathogenicity. Functional splicing assays must be undertaken in order to confirm web-based software predictions of the modification of putative ESE sites by disease-associated mutations.
...
PMID:The effect of disease-associated HRPT2 mutations on splicing. 1933 51

Promoter methylation is a gene- and cancer type-specific epigenetic event that plays an important role in tumour development. As endometrioid (endometrioid endometrial carcinoma, EEC) and serous endometrial cancers (uterine papillary serous carcinoma, UPSC) exhibit different clinical, histological and molecular genetic characteristics, we hypothesized that these differences may be reflected in epigenetic phenomena as well. Identification of a panel of methylation biomarkers could be helpful in a correct histological classification of these two subtypes, which solely on the basis of morphology is not always easy. Methylation-specific multiplex ligation-dependent probe amplification was used to assess the extent of promoter methylation of different tumour suppressor genes in EEC and UPSC. Methylation results were correlated with histology and survival. The median cumulative methylation index of all genes was significantly higher in EEC (124) than in UPSC (93) (P<0.001). Promoter methylation of CDH13 and MLH1 was more frequently present in EEC, while CDKN2B and TP73 were more frequently methylated in UPSC. Almost 90% of EEC and 70% of UPSC could be predicted by CDH13 and TP73. In EEC, methylation of MLH1 was associated with a shorter disease-free survival (DFS; P<0.0001) and overall survival (OS; P=0.005). In a multivariate model, MLH1 methylation emerged as an additional prognostic factor to stage for DFS (P=0.002). In conclusion, promoter methylation is more common in EEC than UPSC. A panel of methylation biomarkers could be useful to distinguish between the two histological subtypes of endometrial cancer. Furthermore, methylation of MLH1 may have prognostic value in EEC.
...
PMID:Methylation profiles of endometrioid and serous endometrial cancers. 2048 83

Hereditary cancer syndromes are frequently seen in young cancer patients and patients with a positive family history. Genetic testing is important for the identification of high-risk individuals, and for the early introduction of specialized preventive care or prophylactic surgeries. High-risk tumour suppressor genes (BRCA1 and BRCA2) and DNA repair genes (MLH1, MSH2 and MSH6) are responsible for a substantial part of hereditary breast, ovarian and colorectal cancer. Other hereditary cancers are seen less frequently, but genetic testing has increased for many other site-specific cancers and complex syndromes. Genetic centres and molecular genetic laboratories are located mostly within university or regional hospitals. Some genetic centres are private. It is highly recommended (Czech Society for Medical Genetics) that all laboratories are accredited according to ISO 15,189 and that genetic testing of hereditary cancer syndromes is indicated by medical geneticists. The indication criteria and prevention strategies were published in Supplement 22 of Clinical Oncology 2009 (in Czech). Preventive care for high-risk individuals is organized by thirteen Oncology Centres, which provide most of the oncology care in the Czech Republic. Genetic testing and preventive care for high-risk individuals and mutation carriers is covered by health insurance. The molecular genetic laboratory at the MMCI provides molecular genetic testing of BRCA1, BRCA2, CHEK2 for hereditary breast/ovarian cancer, MLH1, MSH2, MSH6 for Lynch syndrome,TP53 for Li-Fraumeni syndrome, CDKN2A for familial malignant melanoma syndrome and CDH1 gene for hereditary diffuse gastric cancer. Other syndromes are tested in specialized laboratories elsewhere.The use of genetic testing is increasing because of more frequent referrals from oncologists and other specialists and the increasing variety of genes tested. However, in some patients the testing is not recommended and other family members are dying because of the late diagnosis of hereditary syndrome. Greater awareness of the importance of genetic testing in oncology is needed.
...
PMID:Genetic testing and prevention of hereditary cancer at the MMCI--over 10 years of experience. 2134 12

1 2 Next >>