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

The different proteins of the E-cadherin/catenin cell-cell adhesion complex are believed to play a predominant role in carcinogenesis. Aberrant expression of these proteins has been found in many different human carcinomas, indicating abnormal regulation. In general, inactivating mutations of the human E-cadherin gene are rare; they are, however, highly frequent in infiltrating lobular breast carcinomas and in diffuse gastric carcinomas. These mutations mostly occur in combination with loss of heterozygosity (LOH) of the wild-type allele. Mutations were found at very early non-invasive stages, thus associating E-cadherin mutations with loss of growth control and defining E-cadherin as a real tumour suppressor for these particular tumour types. Defects affecting both alleles of the alpha E-catenin gene have been found in different human carcinoma cell lines, resulting in the loss of E-cadherin-mediated cell-cell adhesion. Mutations of the beta-catenin gene in colon tumours and melanomas were found to result in an accumulation of the protein in the cytosol. Upon translocation to the nucleus, this beta-catenin enhances TCF/LEF-dependent transcriptional activity. This suggests that mutated beta-catenin can act as an oncogene in these particular tumour types. The multiple interaction partners of beta-catenin are known to be involved in signal transduction, actin organization, protein phosphorylation or transcriptional regulation. This makes this protein an intriguing alternative target for either activation or inactivation in human cancer types characterized by frequent E-cadherin or APC deficiencies.
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PMID:Dysregulation of the E-cadherin/catenin complex by irreversible mutations in human carcinomas. 982 69

The Hedgehog (Hh) and Wingless (Wg) signaling pathways play important roles in animal development. The activities of the two pathways depend on each other during Drosophila embryogenesis. In the embryonic segment, Wg is required in anterior cells to sustain Hh secretion in adjacent posterior cells. Hh input in turn is necessary for anterior cells to maintain wg expression. The Hh and Wg pathways are mediated by the transcription factors Cubitus interruptus (Ci) and Pangolin/TCF (Pan), respectively. Coincidentally, pan and ci are adjacent genes on the fourth chromosome in a head-to-head orientation. Our genetic and in situ hybridization data indicate that ciD is a mutation affecting both ci and pan. Molecular analysis revealed that the ciD allele is caused by an inversion event that swapped the promoter regions and the first exons of the two genes. The ci gene in ciD is controlled by the ubiquitous pan promoter and encodes a hybrid Ci protein that carries the N-terminal region of Pan. This domain has previously been shown to bind to the b-catenin homolog Armadillo (Arm), raising the possibility that Wg input, in addition to Hh input, modulates the activity of the hybrid CiD protein. Indeed, we found that Wg signaling induces the expression of the Hh target gene patched (ptc) in ciD animals. We provide evidence that this effect depends on the ability of the CiD protein to bind Arm. Genetic and molecular data indicate that wild-type Pan and CiD compete for binding to Arm, leading to a compromised transduction of the Wg signal in heterozygous ciD/+ animals and to a dramatic enhancement of the gain-of-function activity of CiD in homozygous mutants. Thus, the Hh and the Wg pathways are affected by the ciD mutation, and the CiD fusion protein integrates the activities of both.
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PMID:Drosophila ciD encodes a hybrid Pangolin/Cubitus interruptus protein that diverts the Wingless into the Hedgehog signaling pathway. 985 13

LEF/TCF DNA-binding proteins act in concert with activated beta -catenin, the product of Wnt signaling, to transactivate downstream target genes. To probe the role of activated LEF/TCF transcription factor complexes in hair follicle morphogenesis and differentiation, we engineered mice harboring TOPGAL, a beta -galactosidase gene under the control of a LEF/TCF and beta -catenin inducible promoter. In mice, TOPGAL expression was directly stimulated by a stabilized form of beta -catenin, but was also dependent upon LEF1/TCF3 in skin. During embryogenesis, TOPGAL activation occurred transiently in a subset of LEF1-positive cells of pluripotent ectoderm and underlying mesenchyme. Downgrowth of initiated follicles proceeded in the absence of detectable TOPGAL expression, even though LEF1 was still expressed. While proliferative matrix cells expressed the highest levels of Lef1 mRNAs, LEF1 concentrated in the precursor cells to the hair shaft, where TOPGAL expression was co-induced with hair-specific keratin genes containing LEF/TCF-binding motifs. LEF1 and TOPGAL expression ceased during catagen and telogen, but reappeared at the start of the postnatal hair cycle, concomitant with precortex formation. In contrast to hair shaft precursor cells, postnatal outer root sheath expressed TCF3, but not TOPGAL. TCF3 was also expressed in the putative follicle stem cells, and while TOPGAL was generally silent in this compartment, it was stimulated at the start of the hair cycle in a fashion that appeared to be dependent upon stabilization of beta -catenin. Taken together, our findings demonstrate that LEF1/TCF3 is necessary but not sufficient for TOPGAL activation, revealing the existence of positive and negative regulators of these factors in the skin. Furthermore, our findings unveil the importance of activated LEF/TCF complexes at distinct times in hair development and cycling when changes in cell fate and differentiation commitments take place.
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PMID:Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. 1049 90

Cadherins are transmembrane cell-cell adhesion molecules which are connected to the cytoskeleton by association with the cytoplasmic proteins, alpha-, beta-, and, gamma-catenin (plakoglobin). Beta-catenin has an additional role in the wnt signal transduction pathway in which it transmitts signals to the cell nucleus in complexes with transcription factors of the LEF-1/TCF family. The cell adhesion function of the epithelial E-cadherin is frequently disturbed in carcinomas either by downregulation or by mutation of the E-cadherin/catenin genes. The signaling function of beta-catenin is activated in tumors by mutations of beta-catenin or of the tumor suppressor gene product APC. In this review I will give an introduction to the structure and function of the cadherin/catenin complex and summarize findings which support a decisive role of these components in the development of cancer.
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PMID:Cadherins and catenins: role in signal transduction and tumor progression. 1050 43

The E-cadherin/catenin protein complex regulates the functional integrity of epithelia by mediating specific intercellular adhesion, Defects in the transmembrane E-cadherin protein play an important role in several human cancer types. E-cadherin-inactivating mutations were mainly found in sporadic lobular breast carcinoma and in both familial and sporadic diffuse gastric carcinoma. Armadillo proteins such as beta-catenin and p120ctn are complexed to the cytoplasmic tail of E-cadherin, whereas the vinculin-related alphaE-catenin protein forms a link to the actin cytoskeleton. The latter shows inactivating deletions in various tumor cell lines. Apparently, both E-cadherin and alphaE-catenin serve as tumor suppressor and invasion suppressor molecules. On the other hand, protein-stabilizing oncogenic mutations of beta-catenin were found at high frequency in particular human tumor types. Mutated beta-catenin protein is imported into the nucleus, and its binding to LEF/TCF transcription factors modulates transcription of intriguing target genes. Also p120ctn was recently found to arrive in the nucleus and to interact with a transcription factor. Furthermore, a wide variety of mechanisms have been described to regulate in a reversible way E-cadherin/catenin-mediated cell adhesion and differentiation. These phenomena appear to be crucial in human cancer development and progression.
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PMID:The role of the E-cadherin/catenin adhesion complex in the development and progression of cancer. 1054 29

Lef1 and other genes of the LEF1/TCF family of transcription factors are nuclear mediators of Wnt signaling. Here we examine the expression pattern and functional importance of Lef1 in the developing forebrain of the mouse. Lef1 is expressed in the developing hippocampus, and LEF1-deficient embryos lack dentate gyrus granule cells but contain glial cells and interneurons in the region of the dentate gyrus. In mouse embryos homozygous for a Lef1-lacZ fusion gene, which encodes a protein that is not only deficient in DNA binding but also interferes with (beta)-catenin-mediated transcriptional activation by other LEF1/TCF proteins, the entire hippocampus including the CA fields is missing. Thus, LEF1 regulates the generation of dentate gyrus granule cells, and together with other LEF1/TCF proteins, the development of the hippocampus.
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PMID:Hippocampus development and generation of dentate gyrus granule cells is regulated by LEF1. 1063 Nov 68

The Wnt signal transduction pathway regulates various aspects of embryonal development and is involved in cancer formation. Wnts induce the stabilisation of cytosolic (beta)-catenin, which then associates with TCF transcription factors to regulate expression of Wnt-target genes. At various levels the Wnt pathway is subject to cross-regulation by other components. Recent evidence suggests that a specific MAP kinase pathway involving the MAP kinase kinase kinase TAK1 and the MAP kinase NLK counteract Wnt signalling. In particular, homologues of TAK1 and NLK, MOM-4 and LIT-1, negatively regulate Wnt-controlled cell fate decision in the early Caenorhabditis elegans embryo. Moreover, TAK1 activates NLK, which phosphorylates TCFs bound to (beta)-catenin. This blocks nuclear localization and DNA binding of TCFs. Since TAK1 is activated by TGF-(beta) and various cytokines, it might provide an entry point for regulation of the Wnt system by other pathways. In addition, alterations in TAK1-NLK might play a role in cancer.
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PMID:Cross-regulation of the Wnt signalling pathway: a role of MAP kinases. 1068 40

beta-Catenin and plakoglobin are highly homologous components of cell-cell adherens junctions linking cadherin receptors to the actin cytoskeleton. beta-Catenin, in addition, activates transcription by forming a complex with LEF/TCF family transcription factors in the nucleus. Plakoglobin can also bind to LEF-1 and, when overexpressed in mammalian cells, enhances LEF-1-directed transcription. Plakoglobin overexpression, however, results in the elevation and nuclear translocation of endogenous beta-catenin. We show here, by DNA mobility shift analysis, that the formation of a plakoglobin-LEF/TCF-DNA complex in vitro is very inefficient compared to a complex containing beta-catenin-LEF-DNA. Moreover, in plakoglobin-transfected cells plakoglobin-LEF/TCF-DNA complexes were not formed; rather, the endogenous beta-catenin, whose level is elevated by plakoglobin transfection, formed a beta-catenin-LEF-DNA complex. Removal of the N- and C-terminal domains of both beta-catenin and plakoglobin (leaving the armadillo repeat domain intact) induced plakoglobin-LEF-DNA complex formation and also enhanced beta-catenin-LEF-DNA complexing, both with in vitro-translated components and in transfected cells. Transfection with these truncated catenins increased endogenous beta-catenin levels, but the truncated catenins acted as dominant-negative inhibitors of beta-catenin-driven transcription by forming transcriptionally inactive complexes with LEF-1. When these catenin mutants were prevented from entering the nucleus, by their fusion to the connexin transmembrane domain, they indirectly activated transcription by increasing endogenous beta-catenin levels. These results suggest that overexpression of plakoglobin does not directly activate transcription and that formation of catenin-LEF-DNA complexes is negatively regulated by the catenin N- and C-terminal domains.
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PMID:Differential mechanisms of LEF/TCF family-dependent transcriptional activation by beta-catenin and plakoglobin. 1082 88

Localization of nuclear beta-catenin initiates specification of vegetal fates in sea urchin embryos. We have identified SpKrl, a gene that is activated upon nuclear entry of beta-catenin. SpKrl is upregulated when nuclear beta-catenin activity is increased with LiCl and downregulated in embryos injected with molecules that inhibit beta-catenin nuclear function. LiCl-mediated SpKrl activation is independent of protein synthesis, indicating that SpKrl is a direct target of beat-catenin and TCF. Embryos in which SpKrl translation is inhibited with morpholino antisense oligonucleotides lack endoderm. Conversely, SpKrl mRNA injection rescues some vegetal structures in beta-catenin-deficient embryos. SpKrl negatively regulates expression of the animalizing transcription factor, SpSoxB1. We propose that SpKrl functions in patterning the vegetal domain by suppressing animal regulatory activities.
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PMID:SpKrl: a direct target of beta-catenin regulation required for endoderm differentiation in sea urchin embryos. 1115 35

We showed that the YMB-1-derived breast cancer cell line YMB-S, which proliferates in suspension without aggregation, exhibits complete loss of cell-cell adhesion despite the presence of E-cadherin-catenin complex and expression of free beta-catenin in the cytoplasm. Here, we describe beta-catenin gene regulation, interaction with E-cadherin, immunocytochemical localization, and their relation to growth rate in the YMB-1-derived cell line YMB-A, which forms tight junctions and displays anchorage-dependent growth. YMB-A cells proliferated more slowly than YMB-S cells. E-cadherin and APC gene product expression in YMB-A cells was significantly higher than that in YMB-S cells, whereas expression of beta-catenin, MUC1, and c-myc was lower in YMB-A cells than in YMB-S cells. According to immunocytochemical analysis, beta-catenin in YMB-A cells displayed membranous or submembranous localization, indicating that beta-catenin is mostly tethered to E-cadherin. Inhibition of E-cadherin expression in YMB-A cells by an antisense oligonucleotide did not change expression of whole cell beta-catenin protein, but increased nuclear beta-catenin protein level, c-myc expression, and cell growth rate. These results suggest that decreased expression of E-cadherin and APC and increased amount of beta-catenin in YMB-S cells lead to accumulation of beta-catenin in the nucleus, activate beta-catenin-LEF/TCF signaling pathway, and trigger c-myc proto-oncogene expression. c-Myc overexpression in breast cancer may be related to activated Wnt independent beta-catenin-LEF/TCF signaling.
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PMID:Decreased E-cadherin augments beta-catenin nuclear localization: studies in breast cancer cell lines. 1117 84


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