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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coiled coils serve as dimerization domains for a wide variety of proteins, including the medically important oligomeric tumor suppressor protein, APC. Mutations in the APC gene are associated with an inherited susceptibility to colon cancer and with approximately 75 % of sporadic colorectal tumors. To define the basis for APC pairing and to explore the anatomy of dimeric coiled coils, we determined the 2.4 A resolution X-ray crystal structure of the N-terminal dimerization domain of APC. The peptide APC-55, encompassing the heptad repeats in APC residues 2-55, primarily forms an alpha-helical, coiled-coil dimer with newly observed core packing features. Correlated asymmetric packing of four core residues in distinct, standard rotamers is associated with a small shift in the helix register. At the C terminus, the helices splay apart and interact with a symmetry-related dimer in the crystal to form a short, anti-parallel, four-helix bundle. N-terminal fraying and C-terminal splaying of the helices, as well as the asymmetry and helix register shift describe unprecedented dynamic excursions of coiled coils. The low stability of APC-55 and divergence from the expected coiled-coil fold support the suggestion that the APC dimerization domain may extend beyond the first 55 residues.
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PMID:Crystal structure of the amino-terminal coiled-coil domain of the APC tumor suppressor. 1092 98

Mutations of the tumor suppressor protein APC (Adenomatous Polyposis Coli) are linked to familiar and sporadic human colon cancer. Here we describe a novel interaction between the APC protein and the protein tyrosine phosphatase PTP-BL carrying five PDZ protein-protein interaction domains. Exclusively, the second PDZ domain (PDZ2) of PTP-BL is binding to the extreme C-terminus of the APC protein, as determined by yeast two-hybrid studies. Using surface plasmon resonance analysis we established a dissociation constant (K(D)) of 8.1 x 10(-9) M. We find that a naturally occurring splice insertion of five amino acids (PDZ2b) abolishes its binding affinity to the APC protein. The in vivo interaction between PTP-BL and the APC protein was shown by coprecipitation experiments in transfected COS cells. Furthermore, in cultured epithelial Madine Carnine Kidney cells the subcellular colocalization was demonstrated for the nucleus and also for the tips of cellular extensions. The interaction of the APC protein with a protein tyrosine phosphatase may indirectly modulate the steady state levels of tyrosine phosphorylations of associated proteins, such as beta-catenin playing a major role in the regulation of cell division, migration and cell adhesion.
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PMID:The Adenomatous Polyposis Coli-protein (APC) interacts with the protein tyrosine phosphatase PTP-BL via an alternatively spliced PDZ domain. 1095 83

Phosphoinositide-3-OH kinases (PI(3)Ks) constitute a family of evolutionarily conserved lipid kinases that regulate a vast array of fundamental cellular responses, including proliferation, transformation, differentiation and protection from apoptosis. PI(3)K-mediated activation of the cell survival kinase PKB/Akt, and negative regulation of PI(3)K signalling by the tumour suppressor PTEN (refs 3, 4) are key regulatory events in tumorigenesis. Thus, a model has arisen that PI(3)Ks promote development of cancers. Here we report that genetic inactivation of the p110gamma catalytic subunit of PI(3)Kgamma (ref. 8) leads to development of invasive colorectal adenocarcinomas in mice. In humans, p110gamma protein expression is lost in primary colorectal adenocarcinomas from patients and in colon cancer cell lines. Overexpression of wild-type or kinase-dead p110gamma in human colon cancer cells with mutations of the tumour suppressors APC and p53, or the oncogenes beta-catenin and Ki-ras, suppressed tumorigenesis. Thus, loss of p110gamma in mice leads to spontaneous, malignant epithelial tumours in the colorectum and p110gamma can block the growth of human colon cancer cells.
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PMID:Colorectal carcinomas in mice lacking the catalytic subunit of PI(3)Kgamma. 1167 95

Mutational inactivation of the APC gene is a key early event in the development of familial adenomatous polyposis and colon cancer. APC suppresses tumour progression by promoting degradation of the oncogenic transcriptional activator beta-catenin. APC gene mutations can lead to abnormally high levels of beta-catenin in the nucleus, and the consequent activation of transforming genes. Here, we show that APC is a nuclear-cytoplasmic shuttling protein, and that it can function as a beta-catenin chaperone. APC contains two active nuclear export sequences (NES) at the amino terminus, and mutagenesis of these conserved motifs blocks nuclear export dependent on the CRM1 export receptor. Treatment of cells with the CRM1-specific export inhibitor leptomycin B shifts APC from cytoplasm to nucleus. beta-catenin localization is also regulated by CRM1, but in an APC-dependent manner. Transient expression of wild-type APC in SW480 (APCmut/mut) colon cancer cells enhances nuclear export and degradation of beta-catenin, and these effects can be blocked by mutagenesis of the APC NES. These findings suggest that wild-type APC controls the nuclear accumulation of beta-catenin by a combination of nuclear export and cytoplasmic degradation.
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PMID:Nuclear-cytoplasmic shuttling of APC regulates beta-catenin subcellular localization and turnover. 1098 Jul 7

Epidemiological and animal studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce colon cancer risk. NSAIDs nonselectively inhibit both the constitutive cyclooxygenase (COX) 1 associated with side effects and the desired therapeutic target COX-2, which is induced in inflammation and neoplasia. We used the adenomatous polyposis coli (Apc) mutant Min mouse model to determine whether the selective COX-2 inhibitor celecoxib is effective for adenoma prevention and/or regression, and whether it might be safer than the nonselective NSAID previously shown to be most effective in this model, piroxicam. Min mice (n = 120) were randomized to treatment with celecoxib (0, 150, 500, or 1500 ppm celecoxib mixed in the diet) or piroxicam. To distinguish prevention from regression effects, groups were treated either "early" (before adenomas develop) or "late" (after most adenomas are established). Celecoxib caused dramatic reductions in both the multiplicity and size of tumors in a dose-dependent manner (P < 0.01). Early treatment with 1500 ppm of celecoxib was effective for prevention, decreasing tumor multiplicity to 29% and tumor size to only 17% of controls (P < 0.01). Late treatment demonstrated regression effects, reducing tumor multiplicity and size by about half. In contrast to the significant toxicity of piroxicam, which caused ulcers complicated by perforation and bleeding, celecoxib caused no gastrointestinal side effects and did not inhibit platelet thromboxane B2 at plasma drug levels similar to those obtained in early clinical trials in humans. These results provide the first evidence that selective inhibitors of COX-2 are safe and effective for the prevention and regression of adenomas in a mouse model of adenomatous polyposis and strongly support ongoing clinical trials in humans with the same syndrome. The broader population of patients with common sporadic adenomas that have somatic mutations of the same gene (APC) may also benefit from this treatment approach.
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PMID:The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. 1101 26

The author developed a sensitive yeast-based color assay which expresses APC-ADE2 (reporter) fusion protein in yeast and can screen almost the entire coding region of the APC gene. In this assay, the wild-type APC coding sequence of 8.5 kb is divided into 5 overlapping regions which are respectively ligated in-frame with an ADE2 open reading frame. The resulting five constructs containing a part of wild-type APC gene preserve the ADE2(+) phenotype (white yeast colony) when introduced into the yeast, whereas the yeast transfected with plasmids containing frameshift mutations of the APC gene shows an ADE2(-) phenotype (red yeast colony). Six human colon cancer cell lines were analyzed by this yeast color assay. HCT116 cells with wild-type APC and normal colonic mucosa gave low percentages of red colonies (0-9.9%) in all the regions. On the other hand, more than 96% red colonies were observed in one of the five regions in SW480, Colo201 and Colo320DM cells. Sequence analysis demonstrated the clonal APC mutations at codon 1,338 in SW480, 1,554 in Colo201 and 811 in Colo320DM. Moreover, the assay detected a germline mutation of the APC gene in polyps of a familial adenomatous polyposis (FAP) patient which gave about 50% red colonies. For testing the assay for clinical utilization, 18 colon cancer tissues were subjected to the assay. Eleven cancers (61%) gave more than 10% red colonies (17-57%) and clonal mutations were detected in all these samples. The same mutations were demonstrated in both DNA and RNA samples derived from idendical tissues. These results suggest that this APC yeast color assay is powerful means for detection of APC mutations in clinical samples.
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PMID:[Development of a detection system (APC yeast color assay) of APC mutations by color change of yeast]. 1119 31

beta-catenin was shown to be a major oncoprotein in colon cancer development. Its oncogenic function as a transcriptional activator is upregulated by mutations in the APC tumor suppressor gene, leading to a constitutive activation of the proliferation-associated genes c-myc and cyclin D. The aim of this study was to demonstrate a role of APC-mutations and dysregulated beta-catenin also for the progression of colorectal cancer, by identifying new target genes of beta-catenin associated with tumor invasion and metastasis. Potential invasion genes regulated by beta-catenin and its DNA binding partner TCF4 were identified by a computer search for the consensus DNA binding sequence in relevant promoter regions. Specific DNA binding was confirmed by gel shift assays. Functional importance of beta-catenin for the activation of identified genes was determined by luciferase reporter assays. The significance was demonstrated by coexpression of nuclear beta-catenin and the identified target genes by immunohistochemistry. Among other invasion genes, we identified the matrix metallo proteinases MMP-7 and MMP-1 activated by beta-catenin in the tumor cells. MMP-7 is an important factor for invasion and metastasis and overexpressed in 75% of colon carcinomas. The significance for human colon cancer development was demonstrated by a correlated overexpression of beta-catenin and the MMPs, beginning in large, severely dysplastic adenomas. Our results explain the high percentage of MMP-7 overexpression in colorectal tumors and the resulting activation of invasive growth. Moreover by identifying dysregulated beta-catenin as a transcriptional activator of MMPs and other invasion factors, we demonstrated an important role of mutated APC not only for early steps but also for the progression of colorectal carcinogenesis.
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PMID:[beta-Catenin induces invasive growth by activating matrix metalloproteinases in colorectal carcinoma]. 1121 38

Mutations in the human adenomatous polyposis (APC) gene are causative for familial adenomatous polyposis (FAP), a rare condition in which numerous colonic polyps arise during puberty and, if left untreated, lead to colon cancer. The APC gene is a tumor suppressor that has been termed the "gatekeeper gene" for colon cancer. In addition to the 100% mutation rate in FAP patients, the APC gene is mutated in >80% of sporadic colon and intestinal cancers. The Apc gene in mice has been mutated either by chemical carcinogenesis, resulting in the Min mouse Apcdelta850, or by heterologous recombination, resulting in the Apcdelta716 or Apedelta1368 mice (M. Oshima et al., Proc. Natl. Acad. Sci. USA, 92: 4482-4486, 1995). Although homozygote Apc-/- mice are embryonically lethal, the heterozygotes are viable but develop numerous intestinal polyps with loss of Apc heterozygosity within the polyps (M. Oshima et al., Proc. Natl. Acad. Sci. USA, 92: 4482-4486, 1995). The proinflammatory, prooncogenic protein cyclooxygenase (COX)-2 has been shown to be markedly induced in the Apcdelta716 polyps at an early stage of polyp development (M. Oshima et al., Cell, 87: 803-809, 1996). We demonstrate here that treatment with the specific COX-2 inhibitor rofecoxib results in a dose-dependent reduction in the number and size of intestinal and colonic polyps in the Apcdelta716 mouse. The plasma concentration of rofecoxib that resulted in a 55% inhibition of polyp number and an 80% inhibition of polyps > 1 mm in size is comparable with the human clinical steady-state concentration of 25 mg rofecoxib (Vioxx) taken once daily (A. Porras et al., Clin. Pharm. Ther., 67: 137, 2000). Polyps from both untreated and rofecoxib- or sulindac-treated Apcdelta716 mice expressed COX-1 and -2, whereas normal epithelium from all mice expressed COX-1 but minimal amounts of COX-2. Polyps from either rofecoxib- or sulindac-treated mice had lower rates of DNA replication, expressed less proangiogenic vascular endothelial-derived growth factor and more membrane-bound beta-catenin, but showed unchanged nuclear localization of this transcription factor. This study showing the inhibition of polyposis in the Apcdelta716 mouse suggests that the specific COX-2 inhibitor rofecoxib (Vioxx) has potential as a chemopreventive agent in human intestinal and colon cancer.
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PMID:Chemoprevention of intestinal polyposis in the Apcdelta716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. 1124 90

AIE-75 is a protein identified as an autoantigen in patients with autoimmune enteropathy and as a colon cancer-related antigen. It has recently been assigned to be a causative gene for Usher type 1C congenital syndromic hearing loss. The novel protein has three PSD-95/Dlg/ZO-1 (PDZ) protein-protein interaction domains and is therefore implicated to function as a molecular anchor or sorter. We have identified a novel protein that binds to AIE-75 by yeast two-hybrid screening. The protein has a high homology to the tumor suppressor MCC (mutated in colon cancer; or MCC1 hereafter) and was named MCC2. MCC2 protein binds the first PDZ domain of AIE-75 with its C-terminal amino acids -DTFL. Since the MCC1 does not bind to AIE-75 and the MCC2 displays different expression patterns in various organs compared to MCC1, they appear to play distinct roles in cells. The MCC2 gene is located on chromosome 19p13 in the vicinity of APCL gene, while MCC1 maps near to APC tumor suppressor gene. Because of negative expression of MCC2 in a panel of cancer cell-lines compared to the corresponding normal tissues, we suggest that further study is necessary to investigate a possible role of MCC2 as a tumor suppressor.
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PMID:Interaction of MCC2, a novel homologue of MCC tumor suppressor, with PDZ-domain Protein AIE-75. 1131 60

There is an increasing demand for biomarkers in colon cancer for risk assessment, early detection, prognosis, and surrogate end points. A number of biomarkers have been identified for early detection of colon cancer, although the risk factors have not been identified extensively. The major advances in understanding colorectal cancer include the identification and the involvement of APC, p53, and Ki-ras in the development and progression of the disease, the identification of the aberrant crypt foci as an early preinvasive lesion, and its relation to the development of cancer. Detecting malignant neoplasms in the early stages offers clinical advantages; therefore, the National Cancer Institute has established an Early Detection Research NETWORK: The emphasis of the network is on translational research and collaboration among scientists.
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PMID:Biomarkers for early detection of colon cancer. 1135 Aug 74


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