Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:B0FTZ7 (catenin)
 18,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations of the human adenomatosis polyposis coli (APC) gene are associated with the development of familial as well as sporadic intestinal neoplasia. To examine the in vivo function of APC, 129/Sv embryonic stem (ES) cells were transfected with DNA encoding the wild-type human protein under the control of a promoter that is active in all four of the small intestine's principal epithelial lineages during their migration-associated differentiation. ES-APC cells were then introduced into C57BL/6-ROSA26 blastocysts. Analyses of adult B6-ROSA26<-->129/Sv-APC chimeric mice revealed that forced expression of APC results in markedly disordered cell migration. When compared with the effects of forced expression of E-cadherin, the data suggest that APC-catenin and E-cadherin-catenin complexes have opposing effects on intestinal epithelial cell movement/adhesiveness; augmentation of E-cadherin-beta-catenin complexes produces a highly ordered, "adhesive" migration, whereas augmentation of APC-beta-catenin complexes produces a disordered, nonadhesive migratory phenotype. We propose that APC mutations may promote tumorigenesis by increasing the relative activity of cadherin-catenin complexes, resulting in enhanced adhesiveness and functional anchorage of initiated cells within the intestinal crypt. Our studies also indicate that chimeric mice generated from B6-ROSA26 blastocysts and genetically manipulated ES cells should be useful for auditing gene function in the gastrointestinal tract and in other tissues.
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PMID:Forced expression of the tumor suppressor adenomatosis polyposis coli protein induces disordered cell migration in the intestinal epithelium. 879 Mar 74

Cadherins are a family of calcium-dependent cell-cell adhesion molecules involved in cell-cell aggregation and morphoregulatory cell function. Dysfunction of the cadherin pathway is involved in tumour invasiveness and disease progression for a variety of carcinomas. E-cadherin is a prognostic marker in prostatic cancer, based on the correlation of the grade of E-cadherin expression and tumour grade, stage, metastasis and survival, as well as recurrence after radical prostatectomy. P-cadherin was shown to be lost in all prostatic cancers, although this most likely reflects loss of the basal cell population rather than a transcriptional down-regulation, suggesting that loss of P-cadherin expression is an early event in the tumorigenesis of prostatic carcinomas. Catenins, particularly alpha-catenin, also play an important role in the dysfunction of the cell adhesion complex. Mechanisms of inactivation of the cadherin-catenin pathway include LOH, gene deletions and gene promoter hypermethylation. Therapeutic strategies have been investigated in tumour models, i.e. the use of demethylating agents for the hypermethylated promoter region of E-cadherin or gene transfer in PC-3 cells with homozygous deletion of the alpha-catenin gene. The complexity of neoplastic changes cannot be explained by alterations of cell adhesion molecules alone; but as demonstrated, cadherins and catenins play an important role in this process.
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PMID:The cadherin cell-cell adhesion pathway in prostate cancer progression. 908 71

The E2F group of transcription factors transactivates genes that promote progression through the G1-S transition of the cell cycle. Members of the retinoblastoma (Rb) family of proteins bind to E2Fs and inhibit this function. E2F-4, one example of the E2F group, functions as an oncogene when transfected into nontransformed cells in vitro. On the other hand, mice that are homozygously lacking a normal E2F-1 gene develop cancers, consistent with a tumor-suppressive role for this gene. The exact function of E2Fs has thus been unclear; moreover, direct involvement of this gene in primary human tumorigenesis has not been shown. We, therefore, investigated mutation within the E2F-4 coding region in 16 primary gastric adenocarcinomas, 12 ulcerative colitis-associated neoplasms, 46 sporadic colorectal carcinomas, 9 endometrial cancers, and 3 prostatic carcinomas. We limited our investigation to the serine repeat within E2F-4, reasoning that this tract might be altered in genetically unstable tumors (replication error-positive, or RER+). All tumors were RER+, with the exception of a control group of 15 RER- sporadic colorectal carcinomas. PCR with incorporation of [32P]dCTP was performed using primers flanking the serine trinucleotide (AGC) repeat. Twenty-two of 59 gastrointestinal tumors (37%) contained E2F-4 mutations; these comprised 5 of 16 gastric tumors (31%), 4 of 12 ulcerative colitis-associated neoplasms (33%, including 1 dysplastic lesion), and 13 of 31 sporadic colorectal cancers (42%). No mutation was present in any of the endometrial, prostate, or RER- colorectal tumors. Of note, homozygous mutations occurred in three cases, and two of seven informative patients showed loss of one E2F-4 allele in their tumors. Furthermore, the RER+ sporadic colorectal tumors were evaluated at trinucleotide repeats within the genes for N-cadherin and B-catenin; no tumors demonstrated mutation of these genes. These data suggest that E2F-4 is a target of defective DNA repair in these tumors.
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PMID:Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors. 919 6

Cancer is a chronic and progressive disease characterised by disturbances of growth, cellular differentiation and maintenance of tissue integrity. The latter phenomenon leads to invasion. The transition from the noninvasive towards the invasive stage of the disease is crucial because it transforms a benign and easily curable lesion into a malignant and therapy-resistant disease. Tumour progression is the result of a number of genetic alterations, initiated by a single mutation without immediate clinical manifestations and ending with a metastatic cascade. Activation of tumour-promoter genes (oncogenes), by mutation or overexpression, and inactivation of tumour-suppressor genes, by mutation or deletion, favour oncogenesis. Separate genes are implicated in distinct steps of the tumour progression. Defects in DNA-repair genes influence all steps. Metastasis is a multistep process of invasion. At each step invasion occurs within a micro-ecosystem in which a continuous molecular crosstalk takes place between the cancer cells and the host cells that participate at the establishment of the tumour. The cancer cells carry the genetic alterations and act as the founders of the micro-ecosystem. We shall discuss the invasion-suppressor function of the E-cadherin/catenin complex. Inactivation of one element of this complex may initiate invasion in an appropriate genetic background. Such inactivation may take place at various levels: mutation in coding sequences; hypermethylation of the promoter; mRNA instability; tyrosine phosphorylation; proteolysis; extracellular interactions.
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PMID:[Molecular mechanism of cancer seeding: adhesion molecules and signal transduction networks]. 949 Sep 22

Alterations in the expression or function of molecules that affect cellular adhesion and proliferation are thought to be critical events for tumor progression. Loss of expression of the cell adhesion molecule E-cadherin and increased expression of the epidermal growth factor receptor are two prominent molecular events that are associated with tumorigenesis. The regulation of E-cadherin-dependent cell adhesion by epidermal growth factor (EGF) was therefore examined in the human breast cancer cell line, MDA-MB-468. In this study, changes were observed in the subcellular distribution of components that mediate the cytoplasmic connection between E-cadherin and the actin-based cytoskeleton in response to activation of the EGF receptor. Serum withdrawal activated E-cadherin-dependent cell-cell aggregation in MDA-MB-468 cells, and this treatment stimulated the interaction of actin, alpha-actinin, and vinculin with E-cadherin complexes, despite the absence of alpha-catenin in these cells. By contrast, the co-precipitation of actin with E-cadherin was not detected in several alpha-catenin positive epithelial cell lines. Treatment with EGF inhibited cellular aggregation but did not affect either the levels of E-cadherin or catenin expression nor the association of catenins (beta-catenin, plakoglobin/gamma-catenin, or p120(cas)) with E-cadherin. However, EGF treatment of the MDA-MB-468 cell line dissociated actin, alpha-actinin, and vinculin from the E-cadherin-catenin complex, and this coincided with a robust phosphorylation of beta-catenin, plakoglobin/gamma-catenin, and p120(cas) on tyrosine residues. Furthermore, inactivation of the EGF receptor in serum-treated MDA-MB-468 cells with either a function-blocking antibody or EGF receptor kinase inhibitors mimicked the effects of serum starvation by stimulating both cellular aggregation and assembly of E-cadherin complexes with vinculin and actin. These results demonstrate that the EGF receptor directly regulates cell-cell adhesion through modulation of the interaction of E-cadherin with the actin cytoskeleton and thus substantiates the coordinate role of both of these molecules in tumor progression and metastasis.
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PMID:The epidermal growth factor receptor modulates the interaction of E-cadherin with the actin cytoskeleton. 953 96

Loss of expression and function of the E-cadherin/catenin membrane complex can result in loss of cell adhesion and contribute to invasive or metastatic potential in carcinomas. The aim of this study was to examine the expression of alpha- and beta-catenin and E-cadherin in Barrett's esophagus with and without dysplasia and in esophageal adenocarcinomas and to identify any relationship with tumor growth pattern and clinical outcome. Immunoperoxidase staining for alpha- and beta-catenin and E-cadherin was performed on specimens of Barrett's esophagus with and without dysplasia and on 54 esophageal adenocarcinoma specimens. Membranous staining for all of the components was seen in normal gastric and esophageal mucosa. Abnormal expression of beta-catenin, alpha-catenin, and E-cadherin was significantly associated with higher degrees of dysplasia in Barrett's esophagus. Fourteen of 16 cases of high grade dysplasia and 7 of 7 cases of intramucosal carcinoma showed abnormal expression of beta-catenin, compared with 3 of 6 cases indefinite for dysplasia and 11 of 17 cases with low grade dysplasia (P = 0.022). Similar results were seen for expression of alpha-catenin (P < .01) and E-cadherin (P = .049). In esophageal adenocarcinomas, preserved expression of these proteins occurred more frequently in well-differentiated tumors; abnormal expression was more common in diffusely infiltrative poorly differentiated tumors that did not form glands. Focal nuclear staining for beta-catenin was present in two high-grade dysplasias, two intramucosal carcinomas, and five adenocarcinomas. No survival advantage was demonstrated for patients whose tumors retained expression of these cell adhesion components. In conclusion, abnormal expression of the E-cadherin/catenin membrane complex is common in esophageal adenocarcinoma and occurs early in the dysplasia/carcinoma sequence in Barrett's esophagus, indicating that disturbances in this cell adhesion complex might be important in tumorigenesis and tumor progression in this disorder.
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PMID:Expression of beta-catenin, alpha-catenin, and E-cadherin in Barrett's esophagus and esophageal adenocarcinomas. 975 59

Cell-cell adhesion, as mediated by the cadherin-catenin system, is a prerequisite for normal cell function and the preservation of tissue integrity. With recent progress in our understanding, beta-catenin as a component of a complex signal transduction pathway may serve as a common switch in central processes that regulate cellular differentiation and growth. The function of the cadherin-catenin system in cell adhesion as well as in intracellular signaling, appears to be subjected to multifactorial control by a variety of different mechanisms, and data on a hormonal control of these signaling pathways, even though scarce to date, suggest an important regulatory influence in many cellular systems. Loss of E-cadherin-catenin function was described in many tumors along with an increased invasiveness and a decreased prognosis of many carcinomas, including tumors of endocrine glands and their target systems, and a causal role of this loss-of-function in the multifactorial process of tumorigenesis was recently proven in genetic mouse models. Modification of E-caderin-catenin function in endocrine and nonendocrine tumors may involve germline and somatic gene mutations, epigenetic mechanisms such as gene silencing due to promotor-hypermethylation, and posttranscriptional events, likely to be involved in many endocrine tissues and their target organs. Such events may converge on nuclear activation of oncogenes such as c-myc by the beta-catenin/TCF4 complex. The expression and functional status of the components of the cadherin-catenin system may serve as prognostic markers for endocrine and nonendocrine tumors. The frequent involvement of functional dysregulation in many tumors raises hopes that better definition of the regulation of all components of the cadherin-catenin system and their response to extracellular modulators may eventually lead to new therapeutic approaches for these tumors and help to prevent, more specifically, growth, invasion, and metastasis of these carcinomas.
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PMID:The cadherin-catenin system: implications for growth and differentiation of endocrine tissues. 1020 18

Random homozygous knockout (RHKO) is an antisense RNA strategy capable of identifying genes whose homozygous functional inactivation yields a selectable phenotype in cells growing in culture. Using this approach, we isolated NIH 3T3 fibroblast clones that showed the ability to form colonies on 0.5% agar and tumors in nude mice. The gene inactivated in one of these clones was found to encode VASP (vasodilator-stimulated phosphoprotein), a previously identified protein that binds to components of the cadherin-catenin junctional complex and has been implicated in cell-cell interactions, the formation of actin filaments, and the transmission of signals at the cytoskeleton-membrane interface. Fibroblasts made deficient in VASP by RHKO showed loss of contact inhibition, and consequently, continued cell division past confluence. Restoration of VASP function by reversal of RHKO yielded cells that had lost the neoplastic capabilities acquired during RHKO. Overproduction of VASP mRNA in the sense or antisense orientation from expression constructs introduced by transfection into naive NIH 3T3 fibroblasts also resulted in neoplastic transformation, implying that normal cell growth may require the maintenance of VASP expression within a narrow range. Our results implicate VASP in tumorigenesis and/or cancer progression.
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PMID:Reversible tumorigenesis induced by deficiency of vasodilator-stimulated phosphoprotein. 1020 93

E-cadherin is a member of the cadherin family that plays a major role in epithelial integrity and tumorigenesis. Catenins are a group of cytoplasmic proteins that regulate the intracellular anchorage of cadherin and are required for the linkage between cadherin and the actin cytoskeleton. Loss of E-cadherin contributes to the pathogenesis in tumor invasion and gives a poor prognosis. In order to investigate the adhesion property of intercellular junctions in thyroid tumors, expression of alpha-,beta, and gamma-catenin should also be studied. A correlation between these molecular markers and malignancy would be useful as a preoperative diagnostic test for thyroid neoplasms. The expression of E-cadherin, alpha-, beta-, and gamma-catenin were studied in normal and neoplastic thyroid tissue by immunofluorescence microscopy and Western blot analysis. In the normal thyroid and in nodular goiter, and follicular adenoma, staining for E-cadherin, alpha-, beta-, and gamma-catenin was seen mainly at the lateral surface of epithelial cells in the follicle and the presence of these molecules was confirmed by Western blot analysis. Follicular carcinoma tissue stained positive for E-cadherin and alpha-catenin, but the results of beta- and gamma-catenin immunostaining were highly variable, with beta-catenin being absent in most follicular carcinomas (8/10) and gamma-catenin being absent in some follicular carcinomas (3/10). These results suggest that E-cadherin expression was not reduced during the pathogenesis of differentiated thyroid malignancies. Impairment of the cadherin-catenin complex at the cell junction may contribute to the malignant progression of differentiated thyroid neoplastic tissue.
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PMID:Expression of the cadherin-catenin complex in well-differentiated human thyroid neoplastic tissue. 1059 58

Cadherins are calcium-dependent cell adhesion receptors with strong morphoregulatory functions. To mediate functional adhesion, cadherins must interact with actin cytoskeleton. Catenins are cytoplasmic proteins that mediate the interactions between cadherins and the cytoskeleton. In addition to their role in cell-cell adhesion, catenins also participate in signaling pathways that regulate cell growth and differentiation. Cadherins and catenins appear to be involved in melanocyte development and transformation. Here, we investigated the function of cadherin-catenin complexes in the normal development and transformation of melanocytes by studying the patterns of expression of the cell-cell adhesion molecules, E-, N- and P-cadherin, and the expression of their cytoplasmic partners, alpha-, beta- and gamma-catenin during murine development. Similar analyses were performed in vitro using murine melanoblast, melanocyte, and melanoma cell lines in the presence and absence of keratinocytes, the cells with which melanocytes interact in vivo. Overall, the results suggest that the expression of cadherins and catenins is very plastic and depends on their environment as well as the transformation status of the cells. This plasticity is important in fundamental cellular mechanisms associated with normal and pathological ontogenesis, as well as with tumorigenesis.
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PMID:Plasticity of cadherin-catenin expression in the melanocyte lineage. 1095 94


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