Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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To examine whether the dosage effect of germ-line mutations in patients with familial adenomatous polyposis (FAP) is sufficient to cause colorectal adenomas, or an additional somatic mutation of the normal allele is required as well, we have investigated somatic mutations of the APC gene in multiple adenomas developed in one FAP patient. In addition to a 5-bp deletion of one allele present constitutionally in this patient, the normal APC allele had been lost in five of seven DNA samples extracted from small adenomas (< 3 mm in diameter) with mild or moderate atypia. This result indicates that the inactivation of both alleles of the APC gene is probably essential for the development of an early-stage adenoma, in agreement with the two-hit mutational model underlying the concept of tumor suppressor genes.
Hum Mol Genet 1992 Sep
PMID:Inactivation of both APC alleles in an early stage of colon adenomas in a patient with familial adenomatous polyposis (FAP). 133 60

We examined somatic mutations of the adenomatous polyposis coli (APC) gene in 63 colorectal tumors (16 adenomas and 47 carcinomas) developed in familial adenomatous polyposis (FAP) and non-FAP patients. In addition to loss of heterozygosity (LOH) at the APC locus in 30 tumors, 43 other somatic mutations were detected. Twenty-one of them were point mutations; 16 nonsense and two missense mutations, and three occurred in introns at the splicing site. Twenty-two tumors had frameshift mutations due to deletion or insertion; nineteen of them were deletions of one to 31 bp and three were a 1-bp insertion. One tumor had a 1-bp deletion in an intron near the splicing site. Hence, 41 (95%) of 43 mutations resulted in truncation of the APC protein. Over 60% of the somatic mutations in the APC gene were clustered within a small region of exon 15, designated as MCR (mutation cluster region), which accounted for less than 10% of the coding region. Combining these data and the results of LOH, more than 80% of tumors (14 adenomas and 39 carcinomas) had at least one mutation in the APC gene, of which more than 60% (9 adenomas and 23 carcinomas) had two mutations. These results strongly suggest that somatic mutations of the APC gene are associated with development of a great majority of colorectal tumors.
Hum Mol Genet 1992 Jul
PMID:Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. 133 4

We have identified oncogene-responsive sequences in the human c-fos promoter that mediate induction of transcription by several nonnuclear oncoproteins and the tumor promoter TPA. These sequences are regulated in a cell-specific manner. (i) In NIH 3T3 cells, the CArG box of the c-fos promoter is sufficient to mediate activation by oncogenes. (ii) In contrast, in HeLa cells, additional flanking sequences are also required, including the outer arm of the serum response element and the FAP site. We also show that the serum response factor, which binds to the CArG box, activates transcription in vivo in NIH 3T3 cells but not in HeLa cells. Finally, we present evidence that the intracellular level of the c-Fos protein could be a major determinant of cell-specific regulation of these oncogene-responsive elements of the c-fos promoter.
Mol Cell Biol 1991 Oct
PMID:Cell-specific regulation of oncogene-responsive sequences of the c-fos promoter. 192 53

A DNA element located at positions -295 to -289 of the c-fos promoter (FAP site) is highly homologous to a consensus 12-O-tetradecanoyl phorbol-13-acetate-responsive element (TRE) and to a cyclic AMP (cAMP)-responsive element (CRE). We found that an oligonucleotide containing the FAP element was a transcription regulator which was distinct from both the TRE and CRE. When cloned in multiple copies in front of a reporter gene in HeLa cells, the FAP oligonucleotide was a powerful constitutive activator sequence. Conversely, in the same cells, reporter plasmids containing multiple copies of the TRE of the human metallothionein gene required phorbol esters for their induction. In PC12 cells, the FAP oligonucleotide was cAMP responsive. Its activity was mediated through a cAMP-dependent protein kinase II and did not rely on ongoing protein synthesis for activation. Adenovirus E1a proteins activated viral promoters through ATF (activation transcription factor) consensus binding sequences identical to the CRE. However, E1a repressed the FAP oligonucleotide-associated transcriptional activity in HeLa cells. In PC12 cells, E1a neither transactivated nor transrepressed the basal and cAMP-stimulated FAP activity. In contrast, the CRE of the human c-fos promoter located at -60 was weakly induced by cAMP and E1a in both HeLa and PC12 cells. We suggest that the FAP oligonucleotide acts through a factor(s) distinct from those employed by the TRE and CRE and that the FAP-associated protein factor(s) may differ in HeLa and PC12 cells in expression or posttranslational regulation.
Mol Cell Biol 1990 Dec
PMID:Functional analysis of an isolated fos promoter element with AP-1 site homology reveals cell type-specific transcriptional properties. 214 23

Biopsies of duodenal and ileal mucosa from patients with familial polyposis coli were studied. Areas of atypia were identified in the duodenum of six patients and in the ileum of three patients. Grade I atypia was characterized by crowding and elongation of cells and nuclei, a slight reduction in the number of goblet cells and the presence of a brush border; grade II atypia was further characterized by pseudo- or pluristratification of cells, a marked reduction in the number of goblet cells and the absence of a brush border. In areas of atypia, columnar cells often contained PAS-positive apical granules, which were diastase-resistant and unstained by alcian blue at any pH; the brush border, even where recognizable in haematoxylin-eosin and PAS-stained sections, was unreactive histochemically for alkaline phosphatase. Goblet cells were few in areas of atypia, but those present were regularly stained by PAS and alcian blue pH 2.6. Apical granules, similar in their histochemical characteristics to those observed in columnar cells in areas of atypia, were also found in otherwise normal mucosal areas, even in some patients with no overt areas of atypia in the biopsies studied. These granules have been interpreted as an abnormality, possibly preceding the onset of atypia. Hyperplasia of goblet cells, secreting mucins with the same staining pattern as in normal intestine, was found in some patients, either adjacent to areas of atypia or independent of them. Intervening columnar cells had a normal morphology, alkaline phosphatase-reactive brush borders and no sign of mucus secretion. This goblet cell hyperplasia has been interpreted as a reactive, nonspecific alteration of the mucosa.
Virchows Arch B Cell Pathol Incl Mol Pathol 1986
PMID:Histochemistry of small intestinal dysplasia in familial polyposis coli. 287 28

We report the occurrence of a common five-nucleotide deletion at codon 1309 of the adenomatous polyposis coli (APC) gene in four different South African population groups. The mutation causes familial adenomatous polyposis (FAP) in 18% (4/22 unrelated patients screened) of affected South Africans, which is similar to the frequency described in several other populations. Knowledge of the gene mutation underlying FAP enabled conclusive genetic testing of at-risk family members of four index patients in which this specific mutation has been characterized. The non-radioactive heteroduplex method described in this study allowed cost-effective molecular diagnosis directly after electrophoresis of enzymatically-amplified DNA in agarose gels. The resulting reduction of uncertainty for at-risk relatives is an important benefit of diagnosis at the DNA level.
Mol Cell Probes 1995 Feb
PMID:Screening South African familial adenomatous polyposis families for the five-nucleotide deletion at codon 1309 of the APC gene. 776 Aug 60

An earlier study has shown that FAP patients with mutations in codons 136-302 of the APC gene do not develop congenital hypertrophy of the retinal pigment epithelium (CHRPE), whereas those with mutations in codons 463-1387 regularly do. Here we present data on 36 patients from 20 families with mutations in codons 1445-1578. These patients lack CHRPE. Furthermore, with the exception of three prepubertal children all patients with mutations in codons 1445-1578 developed desmoid tumours. This relationship between certain extracolonic manifestations and site of the APC mutation points to a specific role of the APC protein in different tissues.
Hum Mol Genet 1995 Mar
PMID:Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444. 779 85

The adenomatous polyposis coli (APC) gene, which transmits familial adenomatous polyposis, is frequently mutated in sporadic colorectal tumours. Acquired somatic mutations have also been reported in a second gene, mutated in colorectal cancer (MCC), which lies within 500 kb of APC on chromosome 5q21 and has thus been implicated in tumour development. Further evidence for an oncosuppressor gene other than APC on chromosome 5q comes from recent studies of lung, renal and hepatic cancers in which there is loss of heterozygosity of 5q21 but no somatic APC mutations. To investigate the relative importance of APC and MCC in sporadic colorectal cancer, we have assessed the extent of 5q21 allelic loss in 80 carcinomas. All informative tumours exhibiting allelic loss had deletions which included both APC and MCC. In 21 tumours with loss of heterozygosity in MCC we have screened the entire coding region of the gene for mutation of the retained allele and found no evidence for mutation. The data indicate that independent loss of MCC is a rare event, and that in cases where allele loss occurs mutation of the retained allele is uncommon. This suggests that MCC does not function as an independent tumour suppressor in the majority of colorectal cancers.
Hum Mol Genet 1994 Mar
PMID:Loss of heterozygosity of MCC is not associated with mutation of the retained allele in sporadic colorectal cancer. 801 55

In the course of presymptomatic diagnosis in families with familial adenomatous polyposis (FAP) we screened 202 unrelated patients for mutations in the APC gene. Germ-line mutations were identified in 20.8% of the index patients by a single step screening procedure based on heteroduplex analysis of a PCR product encompassing codons 1027-1384 of the APC gene. The most common mutations in our sample were a 5 bp deletion at codon 1309 in 9% of the families, a 5 bp deletion at codon 1061 in 5% and a 4 bp deletion at codon 1068 in 2.5% of the families. In addition, 11 novel mutations localized within the exons 11-15 of the APC gene were identified by the heteroduplex or SSCP methods.
Hum Mol Genet 1994 Jan
PMID:Frequency of common and novel inactivating APC mutations in 202 families with familial adenomatous polyposis. 816 22

The adenomatous polyposis coli (APC) gene, responsible for familial adenomatous polyposis, is also associated with development of sporadic tumors in digestive system as colon, stomach, or pancreas. In order to investigate whether or not APC mutations occur as an early genetic event during gastric carcinogenesis, we examined somatic mutations of APC in flat adenomas of the stomach. DNAs isolated from flat adenomas were examined by means of an RNase protection analysis coupled with polymerase chain reaction (PCR) followed by DNA sequencing of the PCR products. By screening a mutation cluster region (MCR: codons between 1286 and 1513) of APC in which two-thirds of somatic mutations were detected in colorectal tumors, somatic mutations were found in four of ten flat adenomas: three of which caused truncation of the gene product due to a nonsense mutation or 4-bp deletion; one other was a point mutation that altered amino acid from alanine to threonine. Our results imply that APC plays a crucial role in an early step of gastric carcinogenesis, as was observed in colorectal carcinogenesis.
Hum Mol Genet 1993 Sep
PMID:Somatic mutations of the APC gene in precancerous lesion of the stomach. 824 71


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