Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Deleted in Colorectal Cancer (DCC) gene is a candidate tumour suppressor gene encoding a neural cell adhesion molecule-like transmembrane protein. Over the last year, data supporting DCC inactivation in multiple tumour types have continued to accumulate. Functional studies suggest that DCC may participate in signalling pathways that regulate cell proliferation and/or differentiation, two cellular processes that often go awry during tumorigenesis.
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PMID:DCC: linking tumour suppressor genes and altered cell surface interactions in cancer? 757 91

We have analysed a series of 49 human breast cancers for mutations in the entire coding region plus flanking intron sequences of the E-cadherin gene. The tumours included 41 infiltrating lobular carcinomas, two infiltrating ducto-lobular carcinomas and six infiltrative ductal carcinomas. In the lobular carcinomas 23 different somatic mutations were detected, of which seven were insertions, 11 deletions, two nonsense mutations and three splice site mutations. The other tumours showed no detectable E-cadherin mutations. All the frameshift and nonsense mutations are expected to generate a secreted E-cadherin fragment instead of a transmembrane protein with cell adhesion activity. The majority of the mutations (21 of 23) were found in combination with loss of heterozygosity of the wild type E-cadherin locus (16q22.1), a hallmark of classical tumour suppressor genes. The mutations were scattered over the whole coding region and no hot spots could be identified. All mutations described here were previously unreported. In conclusion, we have identified up to now E-cadherin mutations in 27 of 48 (56%) infiltrating lobular breast carcinomas and in 0 of 50 breast cancers of other histopathological subtypes. These data provide strong evidence that frequent E-cadherin mutations are involved in the particular etiology of sporadic lobular breast cancers.
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PMID:E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. 893 38

The cloning of vertebrate homologues of the Drosophila segment polarity gene patched has led to confirmation of a role for the multipass transmembrane protein which it encodes as a receptor for secreted signalling proteins of the Hedgehog family. In addition, human patched has been identified as a tumour suppressor gene implicated in basal cell carcinomas and medullablastomas.
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PMID:The patched gene in development and cancer. 952 11

Recent investigations revealed microsatellite instability in colon cancers are associated with mutations of the transforming growth factor-beta receptor type II gene (TGF-beta RII) that encodes a transmembrane protein containing an intracellular serine/threonine kinase domain. Activation of TGF-beta receptor type I (RI) and RII by TGF-beta induces nuclear translocation of Smad proteins including Smad2 and Smad4 that have been originally identified as tumour suppressor genes. We have previously reported six cases with microsatellite instability in 32 oesophageal carcinomas. In this study, we analysed genetic mutations of TGF-beta RII, Smad2 and Smad4 in these oesophageal carcinoma tissues and established 16 cell lines. No genetic mutation was detected in any tissues or cell lines except one tissue sample of microsatellite stable oesophageal carcinoma, that is, a mis-sense mutation of glutamic acid to glutamine at codon 526 (E526Q) in the TGF-beta RII serine/threonine kinase domain. Interestingly, the mutant TGF-beta RII E526Q can completely inhibit TGF-beta-induction of nuclear translocation of Smad4 protein in oesophageal carcinoma cells. This mutation of TGF-beta RII that is not associated with microsatellite instability might make a dominant negative effect on TGF-beta signal transduction in oesophageal carcinoma.
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PMID:A dominant negative mutation of transforming growth factor-beta receptor type II gene in microsatellite stable oesophageal carcinoma. 1078 24

The DCC (deleted in colon cancer) gene has a brain restricted high expression pattern. It encodes a transmembrane protein of the immunoglobulin superfamily identified as the netrin-1 receptor. It might be a member of the so called "brain-lymphoid" molecules, which control key cell surface events. To test this hypothesis we have assessed the DCC mRNA level in human normal and malignant myeloid and lymphoid cells. A high mRNA content has been observed only in mature B cells at the secreting or presecreting stage. Expression of DCC was also assessed in the anti-CD40 model of immunopoiesis. Activation of purified tonsillar B cells by anti-CD 40 antibody strongly increased the DCC mRNA level and this effect was dramatically enhanced by the association of IL-2 + IL-10, which is a potent and selective in vitro inducer of the B cell memory phenotype. In contrast no effect has been detected after activation of T cells by anti-CD3. These data suggest that the DCC encoded netrin receptor is involved in B cell immunopoiesis.
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PMID:Upregulation of the netrin receptor (DCC) gene during activation of b lymphocytes and modulation by interleukins. 1135 76

Mutations affecting the transmembrane proteins Patched (Ptc) or Smoothened (Smo) that trigger ligand-independent activity of the Hedgehog (Hh) signalling pathway are associated with human tumours such as basal cell carcinoma (BCC) and medulloblastoma. Despite extensive genetic studies demonstrating the importance of these receptor components in embryonic patterning and cancer, the mechanism by which Ptc regulates Smo is not understood. Here we report that Ptc and Smo are not significantly associated within Hh-responsive cells. Furthermore, we show that free Ptc (unbound by Hh) acts sub-stoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity. Patched is a twelve-transmembrane protein with homology to bacterial proton-driven transmembrane molecular transporters; we demonstrate that the function of Ptc is impaired by alterations of residues that are conserved in and required for function of these bacterial transporters. These results suggest that the Ptc tumour suppressor functions normally as a transmembrane molecular transporter, which acts indirectly to inhibit Smo activity, possibly through changes in distribution or concentration of a small molecule.
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PMID:Patched acts catalytically to suppress the activity of Smoothened. 1219 14

The human PTCH2 gene is highly similar to PTCH1, a tumour suppressor gene frequently mutated in basal cell carcinoma and several other tumour types. PTCH1 is a transmembrane protein believed to inhibit another transmembrane protein SMO (Smoothened), which mediates HH (Hedgehog) signalling. In this study, we analysed the biological properties of several PTCH2 splice variants. An mRNA form that lacked the last exon was abundantly expressed in all tissues examined, in contrast with the one that included it. Moreover, a transcript lacking exon 9, which is a part of a conserved sterol-sensing domain, was identified in intestine, prostate and cerebellum. In ovary, spleen, testis, cerebellum and skin, an mRNA lacking both exons 9 and 10 could also be observed. The different PTCH2 isoforms localized in the cytoplasm were capable of internalizing the N-terminal fragment of Sonic HH (Shh-N). Additionally, the PTCH2 gene was found to be a target of HH signalling. PTCH2 promoter regulation assays demonstrated that only one of the PTCH2 variants could inhibit the activity of SHH-N, whereas none was capable of inhibiting the activated form of SMO (SMO-M2) and this contrasts with PTCH1. Despite the fact that the PTCH2 isoforms lacked the ability to inhibit SMO-M2 activity, all PTCH2 variants as well as PTCH1, on co-transfection with Smo, were able to change Smo localization from being largely dispersed in the cytoplasm to the juxtanuclear region. Furthermore, the PTCH2 isoforms and PTCH1 co-localized in doubly transfected cells and an interaction between them was confirmed using immunoprecipitation assays. Using Ptch1-/- mouse cells, it was shown that the PTCH2 variants and PTCH1 differentially act to reconstitute not only the SHH but also the Desert HH-dependent transcriptional response. We conclude that in spite of their structural similarities, the PTCH2 isoforms have distinct functional properties when compared with PTCH1.
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PMID:Distinct roles of PTCH2 splice variants in Hedgehog signalling. 1461 84

Studies of the HEDGEHOG signalling pathway in Drosophila have revealed a functional link between two genes, cubitus interruptus and patched, whose human homologues are, respectively, a proto-oncogene and a tumour suppressor. While the former has been implicated as a transcription factor, controversy has surrounded the function of the transmembrane protein encoded by the latter. Somewhere in the signal-transduction pathway between these two lies protein kinase A (PKA), and now SMOOTHENED, whose similarity to G-protein-coupled receptors suggests a link with PKA, has also been implicated in the pathway. This article summarizes the current understanding of the pathway and the interactions between these proteins.
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PMID:'Smoothening' the path for hedgehogs. 1515

Using arbitrary primed-PCR (AP-PCR), we have identified a novel genetic alteration located at chromosome 11q23.2 and this genetic alteration was common in 38% of the human Wilms tumour samples analysed. Further characterisation by cloning and sequencing of this genomic region revealed that it represents a part of an uncharacterised gene. We have named this gene as Sporadic Kidney Cancer Gene-1 (SKCG-1). Using fluorescence in situ hybridisation (FISH) approach, we established its localisation on the chromosome 11q23.2. Northern analysis revealed the transcript size of SKCG-1 of 2.09 kb and this was further confirmed by full-length cDNA sequence. Sequence analysis revealed an active translation start site (ATG sequence), a polyadenylation signal sequence (AATAAA), and an open reading frame (ORF) encoding a peptide of 124 amino acids in the cDNA sequence of SKCG-1. Analysis of genomic sequence of SKCG-1 revealed a promoter region containing TATA box located at -13 bp upstream of transcription start site. The AP-PCR, SCAR, and Southern blot analyses indicated genomic loss of SKCG-1 in Wilms tumours. The transcript of SKCG-1 was abundantly present in brain, kidney, liver, testis, salivary gland, foetal brain, foetal liver, whereas relatively lower expression in heart, stomach, prostate and no expression in spleen, colon, lung, small intestine, muscle, adrenal gland, uterus, skin, PBL, and bone marrow was detected. The expression of this gene transcript was either very less or undetectable in Wilms and breast tumours compared to their matched uninvolved tissues. Inhibition of SKCG-1 by siRNA resulted in increased cell proliferation of kidney epithelial cells. Based on the presence of two transmembrane regions in its peptide, SKCG-1 has been predicted as a transmembrane protein. Thus, the findings of this study revealed (i) SKCG-1, a new gene located at 11q23.2 and harbouring genetic alteration in Wilms tumours, (ii) the presence of SKCG-1 gene transcripts in various human normal tissues and its lower expression or absence in Wilms and breast tumours indicate that it may be associated with tumour growth suppressor activity, (iii) the presence of an open reading frame in the cDNA sequence of SKCG-1 indicates that it has potential to encode a protein, (iv) increased cell growth by silencing this gene in HEK293 cells further supports a potential role of this gene in growth of kidney epithelial cells. Our findings suggest that SKCG-1 may have a tumour suppressor role, and implicate genetic alteration in this gene as a potential oncogenic pathway and therapeutic target in kidney and breast cancer.
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PMID:SKCG-1: a new candidate growth regulatory gene at chromosome 11q23.2 in human sporadic Wilms tumours. 1662 58

The survival and growth of individual cells in a tissue can be nonautonomously regulated by the properties of adjacent cells. In mosaic Drosophila imaginal discs, for example, wild-type cells induce the elimination of adjacent slow-growing Minute cells by apoptosis, while, conversely, certain types of faster-growing cells are able to eliminate adjacent wild-type cells. This process, known as cell competition, represents one example of a diverse group of phenomena in which short-range heterotypic interactions result in the selective elimination of one type of cell by another. The mechanisms that designate "winner" and "loser" genotypes in these processes are not known. Here we show that apoptosis is observed preferentially at boundaries that separate populations of cells that express different levels of the transmembrane protein Crumbs (Crb). Cells that express higher levels of Crb tend to be eliminated when they are near cells that express lower levels of Crb. We also observe distortions in the structure of epithelia on either side of boundaries between populations of cells that differ in Crb expression. Thus, while previous studies have focused mostly on the cell autonomous functions of Crb, we show that Crb can regulate cell survival and tissue morphology nonautonomously. Moreover, we find that the extracellular domain (ECD) of Crb, which seems to be dispensable for some of the other characterised functions of Crb, is required to elicit the nonautonomous effects on cell survival. The ECD can also regulate the subcellular localisation of Hippo pathway components, and possibly other proteins, in adjacent cells and may therefore directly mediate these effects. Several genetic lesions alter Crb levels, including loss-of-function mutations in hyperplastic tumour suppressors in the Hippo-Salvador-Warts pathway and in neoplastic tumour suppressor genes, such as scribble. Thus, Crb may be part of a "surveillance mechanism" that is responsible for the cell death that is observed at the boundaries of mutant clones in these cases.
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PMID:Differences in levels of the transmembrane protein Crumbs can influence cell survival at clonal boundaries. 2268 26


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