Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human hMSH2 protein is a member of a highly conserved family of postreplication mismatch repair components found from bacteria to humans. Alterations of the gene coding for this protein cosegregate with, and are the likely cause of, chromosome 2-linked hereditary nonpolyposis colon cancer. Postreplication mismatch repair has been found to faithfully replace misincorporated nucleotides, thereby increasing the overall fidelity of DNA replication. Loss of postreplication mismatch repair function leads to a mutator phenotype, which is proposed to account for the multiple mutations required for multistep carcinogenesis. Although the functions of hMSH2 can be anticipated based on its similarity to well-characterized bacterial and yeast proteins, proof of its functions has not been established. Here we demonstrate that purified hMSH2 binds specifically to mismatched nucleotides, providing a target for the excision repair processes characteristic of postreplication mismatch repair.
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PMID:Purified human MSH2 protein binds to DNA containing mismatched nucleotides. 792 93

The instability of short repetitive sequences in tumor DNA can result from defective repair of replication errors due to mutations in any of several genes required for mismatch repair. Understanding this repair pathway and how defects lead to cancer is being facilitated by genetic and biochemical studies of tumor cell lines. In the present study, we describe the mismatch repair status of extracts of 22 tumor cell lines derived from several tissue types. Ten were found to be defective in strand-specific mismatch repair, including cell lines from tumors of the colon, ovary, endometrium, and prostate. The repair defects were independent of whether the signal for strand specificity, a nick, was 5' or 3' to the mismatch. All 10 defective cell lines exhibited microsatellite instability. Repair activity was restored to 9 of these 10 extracts by adding a second defective extract made from cell lines having known mutations in either the hMSH2 or hMLH1 genes. Subsequent analyses revealed mutations in hMSH2 (4 lines) and hMLH1 (5 lines) that could explain the observed microsatellite instability and repair defects. Overall, this study strengthens the correlation between microsatellite instability and defective mismatch repair and the suggestion that diminuition in mismatch repair activity is a step in carcinogenesis common to several types of cancer. It also provides an extensive panel of repair-proficient and repair-deficient cell lines for future studies of mismatch repair.
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PMID:Microsatellite instability, mismatch repair deficiency, and genetic defects in human cancer cell lines. 852 94

The multistage model of carcinogenesis during tumor progression requires that there should be consecutive genetic abnormalities of both oncogenes and tumor suppressor genes. As is true of the protein products of oncogenes, tumor suppressor proteins are found to have various cellular functions. They are involved in the regulation of adhesion, cell-cell interaction, and cytoplasmic signal transducers as well as nuclear transcription factors. The recently identified hMSH2 (human MutS homolog 2) gene in colorectal carcinomas possesses sequence homologies to DNA mismatch repair genes in bacteria and yeast. An accumulation of evidence exists to indicate the tumor suppressive functions of actin-regulatory proteins. We have shown that both mutant gelsolin His321 and human authentic gelsolin, if expressed at increased levels, may have a suppressive potential against the tumorigenicity of mouse ras-transformed cells (EJ-NIH/3T3). His321 inhibited phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis by phospholipase C gamma 1 more strongly in vitro than did wild-type gelsolin because of its higher binding capacity to phosphoinositide. We have also demonstrated that the production of gelsolin was either lost or notably reduced in human gastric carcinomas and urinary bladder cancers. The cDNAs encoding mouse or human authentic gelsolins were transfected into a urinary bladder cancer cell line. The urinary bladder transfectant lost their tumorigenicity in nude mice. All these and the facts that vinculin, alpha-actinin, erythrocyte band 4.1 family and gelsolin have both tumor-suppressive and phosphoinositides-binding activities in common suggest that these actin-regulatory proteins are a new family of effective tumor suppressors.
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PMID:[Progress of research on tumor suppressor genes]. 864 69

Defects in mismatch repair are associated with several types of cancer. It is also generally believed that environmental carcinogens are responsible for the initiation of cancers by the induction of mutations in critical genes. Prior genetic studies have suggested that the mismatch repair system can also recognize certain forms of DNA damage such as O6-methylguanine and UV photoproducts, and, therefore, mismatch repair may play a role in environmental agent-induced carcinogenesis. To examine this hypothesis, hMutSalpha, a heterodimer which consists of hMSH2 and GTBP and participates in strand-specific mismatch repair, was tested for its ability to recognize DNA containing a site-specific C8-guanine adduct of aminofluorene (AF) or N-acetyl-2-aminofluorene (AAF). We show here that hMutSalpha specifically binds to both AF and AAF adducts. This binding requires both hMSH2 and GTBP. Results from competition and titration experiments indicate that the binding efficiency of hMutSalpha to AF and AAF is about 60% of that to a G-T mismatch, but is at least 10-fold that to an otherwise identical homoduplex DNA without the chemical modification. The specific binding of AF and AAF adducts by hMutSalpha suggests that strand-specific mismatch repair is involved in processing DNA damage induced by environmental carcinogens.
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PMID:Human MutSalpha specifically binds to DNA containing aminofluorene and acetylaminofluorene adducts. 879 46

DNA instability, reflected in altered patterns of short tandem repeat sequences (microsatellites) in dividing cells, has been described in hereditary non-polyposis colon cancer (HNPCC) and in other tumor types. Ovarian cancer (OC), although most often a sporadic cancer, can recur, with HNPCC, as part of the Lynch cancer family syndrome. In an investigation of microsatellite instability (MIN) in 90 OC cases, we found MIN in 3/28 (11%) OC cases with, and 8/62 (13%) without, a family history of cancer. For 2/3 MIN+ OC cases with family cancer history consistent with the Lynch cancer family syndrome, we found additional bands in the microsatellite patterns in tumor versus normal tissue (HNPCC-type of MIN), but no germline mutations in two DNA mismatch repair genes, hMSH2 and hMLH1. In 7/8 MIN+ sporadic OC cases distinct MIN patterns not commonly reported in HNPCC were found. These are characterized by partial or total band shifting, leading to fewer bands and/or changes in the intensity of individual bands restricted to the tumor. In only one case was a germline change in hMSH2 or hMLH1 identified: this was subsequently found to be a polymorphism. An apparent hMLH1 somatic change confined to the tumor was found in another case. The fact that we found no germline pathologic mutations in hMSH2 and hMLH1 (predominant sites of mutation in HNPCC) in MIN+ OC cases, suggests that the genetic basis of MIN in OC can be different from that in HNPCC; our finding that distinct microsatellite banding patterns largely distinguish sporadic from familial OC, may reflect the involvement of different DNA repair genes in MIN in individual OC cases.
Carcinogenesis 1996 Sep
PMID:Microsatellite instability differences between familial and sporadic ovarian cancers. 882 98

The clinical and genetic studies have been very few on a familial predisposition to gastric cancers. We defined the criteria as familial gastric cancer (FGC) in which at least three relatives in two generations have gastric cancers, with one of the relatives having been diagnosed at less than 50 years of age. Other hereditary tumors, such as cancer family syndrome of hereditary nonpolyposis colorectal cancer(HNPCC), should be excluded. To clarify the carcinogenesis in FGC, we examined genetic alterations in six cancers from four FGC kindreds. Four (67%) cancers showed replication error, indicating that microsatellite instability is highly associated with not only HNPCC but also FGC. However, no germline mutation was found in the whole coding sequences of hMSH2 and hMTH1, or in the conservative regions of hMLH1 in any patients. Only few alterations were found at the small repeated sequences in the transforming growth factor-beta type II receptor gene in FGC tumor DNA. These results indicate that the carcinogenetic process of FGC may be different from that of HNPCC.
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PMID:[Analyses of mutator gene mutations in familial gastric cancers]. 892 Jun 67

A genome-wide instability has been found in almost all analyzed malignant tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC), and in a subgroup of sporadic (non-inherited) cancers of the same type. This mutator phenotype was initially seen as novel alleles at microsatellite loci (a family of repetitive DNA sequences) and was shown to be caused by mutations in the highly conserved mismatch repair genes. Mutations have been found in each of four of these human genes: hMSH2, hMLH1, hPMS1 and hPMS2, in the germline of HNPCC patients and in their tumors, as well as in sporadic tumors. These recent discoveries provide new molecular diagnostic tools for the detection of patients at high risk of developing carcinomas of the large bowel and other HNPCC-related tumors. Ongoing international research is progressively solving many of the unanswered questions at the genotypic and phenotypic levels of this newly identified mechanism in carcinogenesis.
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PMID:Microsatellite instability in human solid tumors. 906 3

DNA repair enzymes play a pivotal role in the maintenance of chromosome integrity and in the elimination of premutagenic lesions from DNA by patrolling the genome; nuclear import mechanisms are implicated in molecular carcinogenesis. We have attempted to predict cell trafficking and the nuclear importation of proteins involved in DNA repair by sequence analysis aimed at identifying karyophilic clusters (arginines, lysines, histidines) flanked by the helix breakers proline or glycine that could function as nuclear localization signals (NLSs). Most mammalian proteins that participate in DNA repair pathways seem to possess NLS peptides. Repair proteins with multiple nuclear signals are the ERCC6 helicase (eight signals), the XPC protein involved in the repair of the transcribed strand in active genes (eight strong and seven weak signals), and the Rep-3/Duc-1 mismatch repair protein (five strong one weak signal). We propose that it is unlikely to identify mutations on the genes encoding these proteins resulting in cytoplalsmic retention. However, a number of mammalian DNA repair proteins lack NLS clusters; these proteins include ERCC1, ERCC2 (XPD), mouse RAD51, and the HHR23B/p58 and HHR23A subunits of XPC. NLS-less S. cerevisiae proteins include both RAD51 and RAD52 that function in the recombination and in the repair of double-strand breaks as well as the RAD23 and HRR25 molecules. We propose that these proteins depend on their complexation with other proteins in the cytoplasm for their nuclear localization. The hMSH2 human mismatch repair protein linked to the hereditary nonpolyposis colon cancer gene, has a weak nuclear signal containing two histidines.
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PMID:Nuclear import of DNA repair proteins. 913 18

The mutator hypothesis of tumorigenesis suggests that loss of chromosomal stability or maintenance functions results in elevated mutation rates, leading to the accumulation of the numerous mutations required for multistep carcinogenesis. The human DNA mismatch repair (MMR) genes are highly conserved homologues of the Escherichia coli MutHLS system, which contribute to genomic stability by surveillance and repair of replication misincorporation errors and exogenous DNA damage. Mutations in one of these MMR genes, hMSH2, account for about half of all cases of genetically linked hereditary non-polyposis colorectal cancer. Loss of function of p53 has also been proposed to increase cellular hypermutability, thereby accelerating carcinogenesis, although a clear role for p53 in genomic instability remains controversial. p53 is mutated frequently in a wide range of human cancers, including colonic tumours. Both Msh2- and p53-targeted knockout mice are viable and susceptible to cancer. Here we demonstrate that combined Msh2 and p53 ablation (Msh2-/-p53-/-) results in developmental arrest of all female embryos at 9.5 days. In contrast, male Msh2-/-p53-/- mice are viable, but succumb to tumours significantly earlier (t1-2 is 73 days) than either Msh2-/- or p53-/- littermates. Furthermore, the frequency of microsatellite instability (MSI) in tumours from Msh2-/-p53-/- mice is not significantly different than in Msh2-/- mice. Synergism in tumorigenesis and independent segregation of the MSI phenotype suggest that Msh2 and p53 are not genetically epistatic.
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PMID:Female embryonic lethality in mice nullizygous for both Msh2 and p53. 942 92

Alterations of the length of simple repetitive genomic sequences (microsatellite instability, MSI) characterize a distinct mechanism of colorectal carcinogenesis. Such MSI has been found to be associated with hereditary nonpolyposis colorectal cancer (HNPCC) that involves mutation of the human mismatch repair genes hMSH2 and hMLH1 as well as many sporadic cancers of most tissue types. Although the study of MSI status is a useful tool for HNPCC screening and for the determination of tumor prognosis in sporadic cases of colorectal cancer, the reliability of MSI diagnosis is still a subject of debate. Here we have examined 58 primary colorectal tumors (selected from a cohort of 200) using 31 microsatellite markers that comprised the most frequent simple repeat types. The expression of the hMSH2 and hMLH1 mismatch repair proteins was studied by immunohistochemistry, and most patients were surveyed for at least 2 years. Reproducibility of gel interpretation, as well as diagnostic sensitivity and specificity of the MSI status, were determined. We found that unambiguous determination of band shifts as well as MSI diagnosis were closely related to the type of the marker repeat and that MSI could be subdivided into "high" MSI (>20% unstable loci), "low" MSI (<10% unstable loci), and microsatellite stable (0% unstable loci). One-half of the patients with high MSI tumors (n = 8) fulfilled either the Amsterdam criteria (n = 4), had at least one relative with HNPCC-related carcinoma (n = 2), or were diagnosed with colorectal cancer at an age below 45 years (n = 2). Fourteen of the 15 high MSI tumors had lost either hMSH2 (n = 8) or hMLH1 (n = 6) protein expression. In contrast, all of the low MSI tumors and the MSI-negative tumors displayed normal expression of hMSH2 and hMLH1. These studies provide a clear recommendation for the uniform use of a panel of 10 microsatellites and a definition of at least 40% instability (using these defined marker loci) in the diagnostic analysis of MSI.
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PMID:Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. 935 36


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