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)

Colon carcinomas appear to arise from the cumulative effect of mutations to several genes (APC, DCC, p53, ras, hMLH1, and hMSH2). By using novel colonic epithelial cell lines derived from the Immorto mouse, named the YAMC (young adult mouse colon) cell line, and an Immorto-Min mouse hybrid, named the IMCE (Immorto-Min colonic epithelial) cell line, carrying the Apc min mutation, we investigated the effect of an activated v-Ha-ras gene on tumor progression. The YAMC and IMCE cell lines are normal colonic epithelial cell lines which are conditionally immortalized by virtue of expression of a temperature-sensitive simian virus 40 (SV40) large T antigen. Under conditions which permit expression of a functional SV40 large T antigen (33 degrees C plus gamma interferon), neither the YAMC nor the IMCE cell line grows in soft agar or is tumorigenic in nude mice. In vitro, when the SV40 large T antigen is inactivated (39 degrees C without gamma interferon), the cells stop proliferating and die. By infecting the YAMC and IMCE cell lines with a replication-defective psi2-v-Ha-ras virus, we derived cell lines which overexpress the v-Ha-ras gene (YAMC-Ras and IMCE-Ras). In contrast to the parental cell lines, under conditions in which the SV40 large T antigen is inactive, both the YAMC-Ras and IMCE-Ras cell lines continue to proliferate. Initally YAMC-Ras cells do not form tumors; however, tumors are visible after 90 days of incubation. IMCE-Ras cells form colonies in soft agar under both permissive and nonpermissive culture conditions. Furthermore, IMCE-Ras cells form tumors in nude mice within 3 weeks. The phenotype of the IMCE-Ras cell line thus clearly demonstrates that a defective Apc allele and an activated ras gene are sufficient to transform normal colonic epithelial cells and render them tumorigenic.
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PMID:Synergy between Apc min and an activated ras mutation is sufficient to induce colon carcinomas. 862 90

Presented is a rare case of nonfamilial, hormonally nonfunctional adrenocortical carcinoma with synchronous bilateral adrenal involvement. We investigated adrenal and metastatic tumors for loss of heterozygosity affecting four genetic loci containing the tumor suppressor genes p53, RB, DCC, and APC, using polymerase chain reaction and restriction fragment length polymorphism assay. Allelic losses at the p53 and RB loci were detected in all tumor samples, suggesting that the p53 and RB genes are involved in the tumorigenesis of adrenocortical carcinoma.
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PMID:Bilateral adrenocortical carcinoma showing loss of heterozygosity at the p53 and RB gene loci. 864 Jul 32

Colorectal cancer (CRC) has a strong familial component. Candidate genes for colorectal cancer have been identified through mutations in four mismatch repair genes (hMSH2, hMLH1, hPMS1, and hPMS2) and genes that are deleted or mutated in tumors (DCC, APC, and p53). Linkage analysis of candidate loci/regions was performed in 10 kindreds ascertained for common colorectal cancer from the Utah Population Database. Evidence for linkage to candidate genes was assessed using two- or three-point logarithm of the odds ratio scores with markers spanning the region of localization. One kindred is linked to hMSH2 and also fits the criteria for hereditary nonpolyposis colorectal cancer, having early age of onset and high penetrance for CRC. The remaining nine kindreds are unlinked to the candidate genes tested. These kindreds have a later age of onset and a lower penetrance than hereditary nonpolyposis colorectal cancer kindreds. these results indicate that further unmapped susceptibility loci may be responsible for much of the familial aggregation of CRC.
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PMID:Genetic heterogeneity and unmapped genes for colorectal cancer. 864 Aug 29

Progress in development of a genetic model for colorectal tumorigenesis and human chemoprevention research may allow the mechanism-based identification of targets and chemopreventive agents that will protect against colorectal cancer. For example, numerous mutagenic events can occur throughout colorectal carcinogenesis, including loss of heterozygosity in tumor suppressor genes such as APC, MCC, DCC, and p53, as well as in oncogenes such as K-ras. Chemopreventive agents that inhibit mutagenic activity such as N-acetyl-l-cysteine, oltipraz, and nonsteroidal anti-inflammatory drugs may protect against these mutations. Also, agents such as perillyl alcohol and lovastatin that interfere with protein isoprenylation and, hence, inhibit oncogene activation may protect against aberrant K-ras expression. Hyperproliferation in normal mucosa, leading to growth and progression of neoplasia, are also aspects of colorectal carcinogenesis that can be controlled by chemopreventive agents. Calcium is a chemopreventive agent for which there is both clinical and experimental evidence of inhibition of cell proliferation in colon mucosa. Other examples of antiproliferative agents with potential chemopreventive efficacy in colon are 2-difluoromethylornithine, dehydroepiandrosterone, and selenium. Differentiating agents such as retinoids and deltanoids also may slow proliferation and progression. Antioxidants have potential for interfering with both mutagenicity and proliferation (e.g., by preventing oxidative activation of carcinogens and scavenging activated oxygen species generated during inflammation). The same mechanistic principles apply to identification of dietary chemopreventive intervention for colorectal carcinogenesis. For example, lowering dietary fat and increasing dietary fiber lead to lower colorectal mucosal proliferation, and cruciferous vegetables contain agents such as indoles and dithiolthiones that have shown antimutagenic activity.
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PMID:Genetic and cellular changes in colorectal cancer: proposed targets of chemopreventive agents. 867 84

Forty-nine ovarian tumours were examined for loss of heterozygosity (LOH) on chromosome 5 using eight microsatellite markers spanning both arms, including one at the APC locus. LOH on 5q was a frequent event, detectable in 23 of 49 (47%) tumours, whereas 5p LOH was detected in only 1 of 22 tumours (5%). Six tumours showed partial LOH on 5q, enabling the candidate region to be localised to a 22 cM region proximal to APC, flanked by D5S424 and D5S644. An association was found between 5q LOH and TP53 mutation, with 18 of 23 (78%) tumours with LOH on 5q also harbouring a TP53 mutation. LOH on 5q was observed in 6 of 18 (33%) stage I tumours, suggesting that it may be an early event in the molecular pathogenesis of certain ovarian carcinomas.
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PMID:Loss of heterozygosity on chromosome 5q in ovarian cancer is frequently accompanied by TP53 mutation and identifies a tumour suppressor gene locus at 5q13.1-21. 867 43

Oncogene is not categorized as a tumor marker in a strict sense, however, cancer related oncogens play an important role as a biomarker in hereditary malignant tumors in a wide sense. Various suppressor oncogenes have been identified in the autosomal dominant hereditary diseases such as APC, in familial adenomatous polyposis, p53 in Li-Fraumeni syndrome and BRACA 1 and 2 in breast cancer. By identifying the mutation site or deletions of germ line, it is possible to make a presymptomatic diagnosis of those hereditary malignant tumors. There is splendid progress in understanding of DNA repair mechanism. Recently, the mismatch repair genes were cloned as a causing gene of HNPCC. There are another group of genes called nucleotide excision repair genes which are causative genes of various autosomal recessive hereditary diseases such as xeroderama pigmentation. Pro and cons of presymptomatic diagnosis of familial adenomatous polyposis were discussed in a series of 72 patients among 42 family trees.
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PMID:[Role of tumor marker in the presymptomatic diagnosis of hereditary malignant tumors]. 869 15

The investigation of molecular evidence of gastric carcinoma will be contributable to the prevention, gene diagnosis and therapy of human gastric neoplasms. To determine the specific genetic change in human gastric cancer (HGC) and precancerous lesions, we analysized FISH, PCR/SSCP, IHC and DNA sequencing by using multiple probes to detect the gene abnormalities (mutation, deletion, amplification or overexpression of genes) of 67 fresh tumors, 63 endoscopic biopsies including 30 dysplasia (DYS) and 33 intestinal metaplasia (IM, and 4 tumor cell lines from HGC patients. Multiple genetic abnormalities including hypomethylation of H-ras gene, amplification and overexpression of met and erbB2, deletion of APC, mts1/p16, p53 and nm23 gene and point mutation of p53 gene were noted in HGC and precancerous lesion of human gastric mucosa. Among these changes, p53 gene was the highest frequence genetic alteration in 39/67 (54-58%) of gastric carcinoma. These results indicate that overexpression of met and H-ras occurs at early stage in progression of neoplasia, amplification of met, erbB2 and akt2 gene occurs at progressing stage of tumorigenesis, deletion of p53, APC, mts1/p16 and nm23 occurs at advanced stage in the progression of cancer. The abnormalities should be associated with malignant phenotypes: poor differentiation, vascular invasion, lymph nodes metastasis, and low survival time. We detected p53 gene mutation in both cancer and precancerous lesions of IM and DYS. These results suggest that p53 may be a susceptible gene and alteration of p53 gene plays an important role in the development of HGC.
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PMID:[Multiple gene alterations involved in the processor of human gastric carcinogenesis]. 869 90

Mutation of the APC gene may be a common denominator of all human colon cancer--polypoid and non-polypoid familial cancer as well as sporadic occurrences. Fearon and Vogelstein (1990) have described a series of molecular changes during the progression of human colon cancer, beginning with mutations in APC. Min is a strain of the laboratory mouse carrying a nonsense mutation in Apc, the mouse homologue of APC. The Min strain has been used to test the effect of germline alterations in certain genes identified in the progression pathway of Fearon and Vogelstein. A deficiency in DNA cytosine methylase leads to a reduction in the tumour multiplicity of Min mice contrary to the a priori expectation based on the global hypomethylation of the DNA of early colonic neoplasms. Alterations in Kras had no perceptible effect on the tumour multiplicity of Min mice but may not have been successfully directed to the proliferative cell population. Constitutional mutation of p53 did not influence the multiplicity or histopathology of early Min induced intestinal tumours. The cause and effect analysis of the genetics of colon cancer is clearly in an early phase. An unlinked genetic factor interacting with Min in controlling intestinal tumour multiplicity is Mom1. A central goal for the near future is to identify the Mom1 gene product and to identify other loci that can interact with the Min mutation and affect tumour multiplicity or progression. Mouse chimaeras will permit an analysis of the clonality and cell autonomy of Min induced neoplasms and also of the action of Mom1. The results of these analyses will inform investigators as to what modes of prevention and therapy might be designed for particular tumour types. The Min strain thereby presents an opportunity to discover protective factors against human colon cancer.
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PMID:Emergent issues in the genetics of intestinal neoplasia. 871 26

We have examined 41 cases of follicle centre cell lymphoma with fluorescent PCR of microsatellite repeats closely linked to or within six tumour suppressor gene loci (APC, DCC, P53, RB1, WT1 and NM23). These probes are highly informative with heterozygousity rates in the range of 57%-90%. In addition we have used four loci from chromosome 6 (D6S260, TNFa, D6S281 and D6S262) as control loci which are unlikely to be involved in the pathogenesis of lymphoma. Of 369 informative PCR reactions allele imbalance was identified in 38 (10%) and this was seen in 23 of the 41 cases. Looking at individual loci allele imbalance was seen in APC(1) 11%, APC(2) 12%, P53(1) 5%, P53 (2) 7%, WT1 5%, RB1 13%, DCC 18% and NM23 0%. This frequency of change was no different from that seen at the control loci D6S260 16%, TNFa 20%, D6S281 4% and D6S262 9%. In the indolent phase of germinal centre cell lymphoma there is therefore quite a high rate of allele imbalance at all loci but this is no higher in those loci linked to tumour suppressor genes.
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PMID:Allele imbalance at tumour suppressor loci during the indolent phase of follicle centre cell lymphoma. 872 37

Identification of inherited cancer-predisposing genes offers opportunities for cancer prevention. Inherited susceptibility genes have been identified, primarily through studies of unusual cancer cases and families but also through general population studies. Examples include the RB1 gene for retinoblastoma; the WT1 gene for Wilms' tumor; germline p53 mutations in families with the Li-Fraumeni syndrome; the NF1 and NF2 genes for neuroblastomatosis, types 1 and 2; the VHL gene for renal cancer and other tumors associated with Von Hippel-Lindau disease; the APC gene for adenomatous polyposis coli; the BRCA1 gene for hereditary breast and ovarian cancer; and the mismatch repair genes for colon and other common cancers. For some cancers, identification of gene carriers might be beneficial for targeting screening and chemopreventive interventions. On the other hand, predisposition testing for cancer has the potential for harm from loss of insurability and employability, psychological distress, social stigmatization and other adverse effects. Research is needed to identify predisposition testing procedures that maximize benefits while minimizing harm to subjects. Chemoprevention trials in genetically susceptible populations offer the prospect of finding effective methods of reducing future cancer risk.
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PMID:Identification and management of inherited cancer susceptibility. 874 2


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