Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While it is apparent that colorectal carcinogenesis results from a series of genetic alterations manifested phenotypically by the adenoma-to-carcinoma sequence, the early events that occur in the process of tumorigenesis have not been elucidated. We previously demonstrated that human elongation factor-1 (EF-1) gamma-hybridizing RNA was overexpressed in 25 of 29 colorectal carcinomas. To determine if the overexpression of this mRNA occurs early in tumor development, we examined 25 adenomas and corresponding normal-appearing distant mucosae from 20 patients without familial adenomatous polyposis (FAP). We observed overexpression at a level of twofold or more in 14 (56%) of the 25 adenomas, indicating that overexpression of EF-1 gamma RNA is often a relatively early event in the development of non-FAP colorectal cancer.
Mol Carcinog 1993
PMID:Overexpression of an elongation factor-1 gamma-hybridizing RNA in colorectal adenomas. 838 68

We have detected multiple forms of RNA transcript from APC, the gene which is responsible for familial adenomatous polyposis (FAP). Transcriptional initiation occurs at three sites in two distinct non-translating exons at the 5' end of the gene. At least five different forms of 5' non-coding sequences, generated by alternative splicing, exist. The splicing mechanism seems to be regulated in a tissue-specific fashion, and one type of transcript contained an additional exon, which was transcribed specifically in brain. Analyses of mRNAs from two colorectal-tumor cell lines by reverse-transcriptase polymerase chain reaction (RT-PCR) revealed that one or another of the transcriptional forms was absent in both cell lines. This observation suggested the presence of mutations in the control region or the first exon of APC, or that mutation(s) could have affected the splicing efficiency or transcriptional initiation of the gene in these tumors. Furthermore, we found that the alternative splicing involving the 19 kDa protein of signal recognition particle (SRP19) gene, that is known to occur at exon 14 of APC, is also controlled in a tissue-specific manner, and one type of transcript lacked in some organs.
Hum Mol Genet 1993 Mar
PMID:Multiple forms of the APC gene transcripts and their tissue-specific expression. 838 66

Germ-line mutations in the adenomatous polyposis coli (APC) gene result in familial adenomatous polyposis coli (APC), an inherited syndrome that predisposes affected individuals to early onset of colorectal cancer. Somatic APC mutations also have been detected in sporadic colon tumors. We have used single strand conformational polymorphism (SSCP) analysis to scan a region of the APC gene that frequently is mutated in both APC and sporadic colorectal cancer. Four truncating mutations were found between codons 1060 and 1327 in 17 of 68 unrelated APC individuals. Fourteen of these persons carried either of two previously described five-nucleotide deletions which represent about 20% of APC mutations in these pedigrees. Patients with mutations in this region of exon 15 develop a classic APC colonic phenotype with multiple, diffuse adenomas developing by the second or third decade. However, the density of adenomas and the extracolonic disease manifestations associated with this syndrome are variable among individuals with identical APC mutations.
Hum Mol Genet 1993 Jul
PMID:Identical APC exon 15 mutations result in a variable phenotype in familial adenomatous polyposis. 839 41

Damage to the human adenomatous polyposis coli (APC) gene is responsible for not only familial adenomatous polyposis but also many sporadic cancers of the entire digestive tract. Using homologous recombination in embryonic stem cells, we recently constructed gene knockout mice with a truncation mutation in the Apc gene. These heterozygous mice developed intestinal polyps. We found that all microadenomas dissected from the earliest polyps had already lost the wild-type allele, indicating loss of heterozygosity (LOH) (Oshima et al., Proc. Natl. Acad. Sci. USA 92:4482-4486, 1995). Using these knockout mice, we investigated the effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP), one of the most abundant heterocyclic amines found in cooked meat and fish. When PhIP was fed to these mice at 400 ppm for 8 wk, the polyp distribution shifted to a larger size range, although the total polyp number did not change significantly. Similar, but weaker, effects were observed with the other heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. On the other hand, intraperitoneal injections of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhlP) at a higher dose (50 mg/kg) for five consecutive days increased the polyp number significantly. This increment was not associated with mutations in the Apc gene; however, most polyps showed loss of the full-length Apc allele (LOH). These results suggest that PhIP affects intestinal polyp development by accelerating the growth rate of microadenomas. It is also possible that high doses of N-OH-PhIP increase the frequency of Apc gene LOH.
Mol Carcinog 1996 Jan
PMID:Effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine on intestinal polyp development in Apc delta 716 knockout mice. 856 61

Endothelin-1 (ET-1) triggers poorly understood nuclear signaling cascades that control gene expression, cell growth, and differentiation. To better understand how ET-1 regulates gene expression, we asked whether voltage-insensitive Ca2+ channels and Ca2+/calmodulin-dependent protein kinases (CaMKs) propagate signals from ET-1 receptors to the c-fos promoter in mesangial cells. Ca2+ influx through voltage-insensitive Ca2+ channels, one of the earliest postreceptor events in ET-1 signaling, mediated induction of c-fos mRNA and activation of the c-fos promoter by ET-1. A CaMK inhibitor (KN-93) blocked activation of the c-fos promoter by ET-1. Ectopic expression of CaMKII potentiated stimulation by ET-1, providing further evidence that CaMKs contribute to c-fos promoter activation by ET-1. The c-fos serum response element was necessary but not sufficient for CaMKII to activate the c-fos promoter. Activation of the c-fos promoter by ET-1 and CaMKII also required the FAP cis element, an AP-1-like sequence adjacent to the serum response element. Thus, voltage-insensitive Ca2+ channels and CaMKs apparently propagate ET-1 signals to the c-fos promoter that require multiple, interdependent cis elements. Moreover, these experiments suggest an important role for voltage-insensitive Ca2+ channels in nuclear signal transduction in nonexcitable cells.
Mol Cell Biol 1996 Oct
PMID:Voltage-insensitive Ca2+ channels and Ca2+/calmodulin-dependent protein kinases propagate signals from endothelin-1 receptors to the c-fos promoter. 881 5

This study compared colonoscopic findings in families meeting the Amsterdam criteria (A) for hereditary non-polyposis colorectal cancer (HNPCC) but stratified according to whether the familial cancers showed DNA microsatellite instability. DNA was extracted from paired samples of normal and cancer, and microsatellite instability was analysed at up to six loci. Families were termed replication error positive (RER+) when at least 50% of tumours tested per family were positive. Of 26 families studied 17 were RER+ and 9 were RER-. Cancers in the A/RER- families showed no right-sided predilection (P < 0.001). Colonoscopies have been performed on 182 at-risk members of A/RER+ families and 60 members of A/RER- families. More of the at-risk members of A/RER-families were found to have adenomas at colonoscopy (P = 0.095), but these were smaller than those of A/RER+ families (P = 0.19). The adenoma:carcinoma ratio was twice as high in A/RER- families (13:1) as in A/RER+ families (7:1). One of the A/RER- families had hyperplastic polyposis. The others do not appear to have attenuated familial adenomatous polyposis and are similar to the adenoma families or late-onset colorectal cancer families described by others. This study illustrates the importance of molecular technology in separating HNPCC from syndromes with overlapping phenotypes.
J Mol Med (Berl) 1996 Sep
PMID:Colorectal neoplasms detected colonoscopically in at-risk members of colorectal cancer families stratified by the demonstration of DNA microsatellite instability. 889 60

Mutations in the APC gene are responsible for the dominantly inherited colon cancer syndrome, familial adenomatous polyposis (FAP). We have designed PCR primers which allow amplification by RT-PCR of exons 1-14 of the APC gene in six overlapping segments. The amplicons have been screened for the presence of mutations in patients affected with FAP using heteroduplex analysis. One patient has been identified with an alternatively spliced transcript involving exon 14 and a single base insertion mutation within the same exon.
Mol Cell Probes 1996 Oct
PMID:Mutation detection in exons 1-14 of the adenomatous polyposis coli gene: identification of an alternatively spliced transcript. 891 Aug 93

Desmoid tumours are generally very rare but occur about 100 times more frequently in the colorectal cancer predisposition syndrome familial adenomatous polyposis (MIM 175100), being represented in about 10% of patients. In addition to desmoid disease occurring in familial adenomatous polyposis (FAP) there exist familial infiltrative fibromatosis (MIM 135290) kindreds where there is no evidence of FAP. Previously we have described a kindred with familial infiltrative fibromatosis (FIF) in which desmoid tumours were associated with nonpolyposis colorectal cancer. FAP is caused by mutations in the APC gene and various genotype-phenotype relationships have been defined including reports that colorectal polyposis is less severe with mutations 5' to codon 157 and that the risk of desmoid tumours is high in FAP patients with APC gene mutations between codons 1444 and 1598. There is relatively little information on the phenotype of APC gene mutations 3' to codon 1598; however, one large family has been reported with a mutation at codon 1987 which presents with a highly variable phenotype which includes desmoid disease. We screened our original FIF kindred and three further families with a similar phenotype for mutations in the APC gene. A 4 bp frameshift deletion in codon 1962 was identified in the original FIF kindred and two further apparently unrelated families. Haplotype analysis suggests a common origin for the APC mutation in all three families. Affected individuals had no evidence of congenital hypertrophy of the retinal pigment epithelium. Colorectal polyposis was variable, and most affected patients had either none or a few late onset polyps. These findings demonstrate (i) that FAP and FIF are allelic, and (ii) that APC gene mutations which truncate the APC protein distal to the beta-catenin binding domain are associated with desmoid tumours, absent CHRPE and variable but attenuated polyposis expression.
Hum Mol Genet 1996 Dec
PMID:Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3' APC gene mutation. 896 44

We examined the expression of matrilysin mRNA in sporadic and hereditary colorectal adenomas to clarify the role of matrilysin in tumorigenesis. Matrilysin mRNA was not detected in normal colorectal mucosa from patients with either sporadic or familial adenomas. Matrilysin mRNA expression in sporadic adenomas correlated with the degree of dysplasia and the size of the mass, whereas most of the adenomas in patients with familial adenomatous polyposis coli expressed matrilysin mRNA irrespective of adenoma size or degree of dysplasia. Because matrilysin is more likely to be expressed in adenomas with a potential for malignancy, this enzyme may play a role in the malignant conversion of colorectal adenomas.
Mol Carcinog 1997 Aug
PMID:Matrilysin gene expression in sporadic and familial colorectal adenomas. 929 Jun 98

Although in vitro protein synthesis is a rapid method to screen for translational stops in the adenomatous polyposis coli (APC) gene, truncating mutations at the 5' most end are at risk of being overseen due to their small size. The authors describe a reverse transcriptase-polymerase chain reaction (RT-PCR)-based protein truncation test specifically designed for detecting truncated polypeptide chains of less than 10 kDa. Using this detection system, three novel germline mutations in familial adenomatous polyposis (FAP) patients were identified, i.e. a Gly101 Ter non-sense mutation in exon 3, an exon 4 splice acceptor mutation and a 555delC deletion in exon 5. Morever, a patient manifesting congenital hypertrophy of the retinal pigmented epithelium (CHPRE) was detected with an Arg232Ter mutation in exon 6. This is, to the authors' knowledge, the fourth exception to the rule that FAP patients manifesting CHRPE harbour genetic alternations downstream from APC exon 9. Hence, an alternative hotspot for non-sense mutations associated with CHRPE appears to encompass the codons 215, 216 and 232. Patients reported in this study, exhibited relatively mild clinical symptoms with respect to the age of onset of malignancy (> 50 years of age) and the number of polyps (70-100 adenomas). However, manifestation of severe duodenal adenomatosis was independent of the attenuated colorectal FAP phenotype.
Mol Cell Probes 1998 Jun
PMID:Rapid RT-PCR-based protein truncation test in the screening for 5' located mutations of the APC gene. 966 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>