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)

Analysis of the calcium-dependent cell adhesion molecule E-cadherin has led to the identification of catenins, which are necessary for cadherin function. Growing evidence that cadherins and catenins are subjected to genetic alterations in carcinogenesis makes it especially important to understand protein-protein interactions within the cadherin-catenin complex. Here we report the identification and analysis of the alpha-catenin binding site in plakoglobin (gamma-catenin). Using N- and C-terminal truncations of plakoglobin, we identified a domain of 29 amino acids necessary and sufficient for binding alpha-catenin. The alpha-catenin binding site is fully encoded within exon 3 of plakoglobin but only partially represented in Armadillo repeat 1. This suggests that exons rather than individual Arm repeats encode functional domains of plakoglobin. Site-directed mutagenesis identified residues in the alpha-catenin binding site indispensable for binding in vitro. Analogous mutations in beta-catenin and Armadillo had identical effects. Our results indicate that single amino acid mutations in the alpha-catenin binding site of homologs of Armadillo could prevent a stable association with alpha-catenin, thus affecting cadherin-mediated adhesion.
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PMID:Single amino acid substitutions in proteins of the armadillo gene family abolish their binding to alpha-catenin. 857 47

Members of the epidermal growth factor (EGF) receptor family are known to be specifically involved in mammary carcinogenesis. As a nuclear target of activated receptors, we examined c-Jun in mammary epithelial cells. For this, we used a c-JunER fusion protein which was tightly controlled by estrogen. Activation of the JunER by hormone resulted in the transcriptional regulation of a variety of AP-1 target genes. Hormone-activated JunER induced the loss of epithelial polarity, a disruption of intercellular junctions and normal barrier function and the formation of irregular multilayers. These changes were completely reversible upon hormone withdrawal. Loss of epithelial polarity involved redistribution of both apical and basolateral proteins to the entire plasma membrane. The redistribution of E-cadherin and beta-catenin was accompanied by a destabilization of complexes formed between these two proteins, leading to an enrichment of beta-catenin in the detergent-soluble fraction. Uninduced cells were able to form three-dimensional tubular structures in collagen I gels which were disrupted upon JunER activation, leading to irregular cell aggregates. The JunER-induced disruption of tubular structures was dependent on active signaling by growth factors. Moreover, the effects of JunER could be mimicked in normal cells by the addition of acidic fibroblast growth factor (aFGF). These data suggest that a possible function of c-Jun in epithelial cells is to modulate epithelial polarity and regulate tissue organization, processes which may be equally important for both normal breast development and as initiating steps in carcinogenesis.
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PMID:The estrogen-dependent c-JunER protein causes a reversible loss of mammary epithelial cell polarity involving a destabilization of adherens junctions. 860 89

A protein first identified by its association with cadherin cell adhesion molecules, beta-catenin, has been implicated in carcinogenesis. In a number of different types of cancer, signalling through beta-catenin is upregulated either by direct mutation of beta-catenin or loss of negative regulation by the APC tumor suppressor protein.
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PMID:Carcinogenesis: a balance between beta-catenin and APC. 921 Mar 68

E-cadherin is crucial to the intercellular adherens junctions which are involved in the organisation and maintenance of epithelial structure and suppression of tumour invasion. E-cadherin is associated with the actin cytoskeleton via cytoplasmic proteins, including alpha-, beta- and gamma-catenins, which together form the cadherin/catenin complex. To evaluate changes of the molecules of the cadherin/catenin complex in colorectal carcinogenesis, seventy-four sporadic adenomas, samples of histologically normal epithelium adjacent to 65 adenomas, and 52 carcinomas arising in adenomas were investigated by immunohistochemistry. All normal epithelial cells showed a uniform membranous staining pattern for E-cadherin, alpha-, beta-, and gamma-catenin. Decreased expression of all 4 proteins occurred in parallel in adenomas and carcinomas (in all cases, p < 10(-5). Decreased expression of the cadherin/catenin complex in adenomas was associated with increasing severity of dysplasia (p < 0.001, for E-cadherin, alpha-, and gamma-catenin, p < 0.005 for beta-catenin). Carcinomas displayed significantly reduced expression of the cadherin/catenin complex compared with their associated adenomas (all p < 0.001). The results directly confirm that colorectal tumour progression and invasion is associated with disruption of the cadherin/catenin complex and suggest that the genetic changes and transcriptional modulation of catenins underlying this progression may affect all members of the complex.
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PMID:Reduced expression of molecules of the cadherin/catenin complex in the transition from colorectal adenoma to carcinoma. 921 95

Mutations of tumor suppressor genes, of the mismatch DNA repair system, and of the TGF-beta-II-receptor are the main causes for a higher risk of colorectal cancer. Among mutations of the Ape gene, which characterize the clinical manifestation of the familial polyposis (FAP), point mutations are dominating which create new stop codons or arise from deletions or insertions of nucleotides causing frame shifts. Because the binding site of beta-catenin is localized in the C-terminus of the Ape protein, disturbances result in the cellular signal transfer from its loss. Consequently, the interactions of the usually formed Ape-beta-catenin complex with the cytoskeleton and the cadherin system in the plasma membrane as well as the translocation of beta-catenin into the nucleus cannot be realized. Mutations in the genes of the mismatch DNA repair system and of the TGF-beta-II-receptor, the main defects of the HNPCC (hereditary nonpolyposis colorectal cancer), are exclusively identified in sequences of microsatellites. Because the majority of Apc gene mutations is also localized in repetitive motifs even in CpG islands primary disturbances are to postulate in the methylation pattern of the genes producing germline and somatic mutations. Generally, complexly connected reactions are involved in this cascade of colorectal cancer genesis. This fact explains the relatively late clinical manifestation of the disease and offers the possibility to identify carriers with an increased risk of colorectal cancer development in order to integrate them into a programme of control and preventive medicine. Beside the known treatment by surgery and cytostatics, inhibitors of prostaglandin synthesis gain therapeutic significance. Cancerogenesis can be efficiently suppressed by inhibition of the COX-2-induction (cyclo-oxygenase-2). There is a lack of clinical experience for a decision whether a high intraluminal level of butyrate in the large intestine can delay colorectal carcinogenesis.
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PMID:[Molecular etiology of colorectal carcinogenesis, clinical manifestations and therapy]. 924 53

The E-cadherin-catenin adhesion complex has been the subject of many structural and functional studies because of its importance in development, normal tissue function and carcinogenesis. It is well established that the cytoplasmic domain of E-cadherin binds either beta-catenin or plakoglobin, which both can assemble alpha-catenin into the complex. Recently we have identified an alpha-catenin binding site in beta-catenin and plakoglobin and postulated, based on sequence analysis, that these protein-protein interactions are mediated by a hydrophobic interaction mechanism. Here we have now identified the reciprocal complementary binding site in alpha-catenin which mediates its interaction with beta-catenin and plakoglobin. Using in vitro association assays with C-terminal truncations of alpha-catenin expressed as recombinant fusion proteins, we found that the N-terminal 146 amino acids are required for this interaction. We then identified a peptide of 27 amino acids within this sequence (amino acid positions 117-143) which is necessary and sufficient to bind beta-catenin or plakoglobin. As shown by mutational analysis, hydrophobic amino acids within this binding site are important for the interaction. The results described here, together with our previous work, give strong support for the idea that these proteins associate by hydrophobic interactions of two alpha-helices.
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PMID:A specific domain in alpha-catenin mediates binding to beta-catenin or plakoglobin. 926 63

beta-catenin plays a central part in cell adhesion as a structural component of the cadherin complex. In a seemingly disparate role, it is also important in embryo patterning, and now has emerged as a leading actor in carcinogenesis. beta-catenin achieves its diverse functions by interacting with many partners. The recent structure of the core domain from beta-catenin suggests how this talented molecule can achieve its many functions.
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PMID:The multi-talented beta-catenin makes its first appearance. 935 13

Beta-Catenin is a key regulator of the cadherin-mediated cell-cell adhesion system and an important element in the Wnt signal transduction pathway. Stabilization and accumulation of cytoplasmic beta-catenin, which result from mutations in either the adenomatous polyposis coli or beta-catenin genes, are causatively associated with colon carcinogenesis. In the present study, we examined the expression of beta-catenin in rat colon tumors induced by azoxymethane in comparison with adjacent normal colon mucosa by immunostaining and immunoblotting. Cytoplasmic and nuclear immunostaining was pronounced in all colon adenoma and carcinoma tissues, whereas antibody binding was limited to membranes at the intercellular borders in normal colon epithelial cells. Increase of the free beta-catenin fraction in tumor cells was also indicated by immunoblot analysis of fractionated tissue lysates. Investigation of mutations in the glycogen synthase kinase-3beta phosphorylation consensus motif of the beta-catenin gene by PCR-single strand conformation polymorphism methods and direct sequencing revealed eight mutations in six of the eight colon carcinomas, and seven of these were shown to be G:C to A:T transitions, with five being CTGGA to CTGAA. Such frequent mutations of the beta-catenin gene in azoxymethane-induced rat colon tumors suggest that consequent alterations in the stability and localization of the protein may play an important role in this colon carcinogenesis model.
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PMID:Beta-catenin is frequently mutated and demonstrates altered cellular location in azoxymethane-induced rat colon tumors. 942 55

Activating mutations in the beta-catenin (CTNNB1) gene corresponding to N-terminal phosphorylation sites in the protein have been implicated in the development of human colon cancer. To determine the possible involvement of such mutations during chemically induced colon carcinogenesis, we examined the corresponding region of Ctnnb1 in colon tumors induced in the F344 rat by two cooked meat heterocyclic amines, 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). All of the colon tumors induced by 2-amino-3-methylimidazo[4,5-f]quinoline that were examined (5 of 5) and 4 of 7 PhIP-induced colon tumors had mutations within or flanking codons corresponding to important phosphorylation sites in beta-catenin. None of the colon tumors bearing Ctnnb1 mutations had genetic changes in the Apc gene, and those that contained wild-type Ctnnb1 were known from our previous work to contain Apc mutations. The results provide evidence for a major role of the beta-catenin/Apc pathway in the development of heterocyclic amine-induced colon tumors and give further weight to the view that regulation of beta-catenin is critical to the tumor suppressive effects of Apc during colon carcinogenesis. In contrast, Ctnnb1 mutations were completely absent in 23 PhIP-induced mammary tumors, in accordance with recent work showing that human breast carcinomas lack mutations in CTNNB1.
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PMID:High frequency of beta-catenin (ctnnb1) mutations in the colon tumors induced by two heterocyclic amines in the F344 rat. 951 94

The adenomatous polyposis coli (APC) gene has been found to be mutated during the development of sporadic colorectal cancers as well as in familial adenomatous polyposis (FAP). These conditions result from initially somatic and germ line mutations respectively. In both cases, the expressed protein is truncated at its carboxyterminal region. Investigations into the role of wild-type APC have led to a better understanding of the importance of mutations in the genesis and progression of adenomas. APC was shown to regulate cell growth and cell death, to bind beta-catenin, and to colocalize with microtubules. APC truncation was therefore hypothesized to alter cell multiplication and cells are no longer able to undergo apoptosis. Owing to its beta-catenin binding, APC can modify the pool of beta-catenin which is in part utilized in the assembly of adherens junctions and in nuclear signalling. Truncated APC is unable to regulate this pool thereby altering adhesion and cell signalling. Finally, APC involvement in microtubule-dependent locomotion may explain some changes in cell movement which are observed in adenomas. The establishment of murine mutants and of normal and malignant intestinal cell cultures have allowed to assess biochemical and physiological properties of APC and its putative role in the genesis of colorectal carcinogenesis. Moreover, these experimental models have suggested a variety of possible therapeutic approaches.
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PMID:[Current data on the role of APC protein in the origin of colorectal cancer]. 953 87


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