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Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors.

Artikel i vetenskaplig tidskrift
Författare Fredrik Enlund
Afrouz Behboudi
Ywonne Andrén
Camilla Öberg
Urban Lendahl
Joachim Mark
Göran Stenman
Publicerad i Experimental cell research
Volym 292
Nummer/häfte 1
Sidor 21-8
ISSN 0014-4827
Publiceringsår 2004
Publicerad vid Institutionen för laboratoriemedicin , Avdelningen för patologi
Sidor 21-8
Språk en
Länkar dx.doi.org/10.1016/j.yexcr.2003.09....
Ämnesord Adenolymphoma, metabolism, Animals, Artificial Gene Fusion, COS Cells, Carcinoma, Mucoepidermoid, genetics, metabolism, Cell Line, Tumor, Cercopithecus aethiops, Chromosome Mapping, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 19, Cloning, Molecular, Exons, Gene Deletion, Gene Expression Regulation, Neoplastic, Green Fluorescent Proteins, Humans, Karyotyping, Luminescent Proteins, metabolism, Membrane Proteins, metabolism, Receptors, Notch, Salivary Gland Neoplasms, genetics, metabolism, Signal Transduction, Translocation, Genetic
Ämneskategorier Medicin och Hälsovetenskap

Sammanfattning

Chromosome translocations in neoplasia commonly result in fusion genes that may encode either novel fusion proteins or normal, but ectopically expressed proteins. Here we report the cloning of a novel fusion gene in a common type of salivary and bronchial gland tumor, mucoepidermoid carcinomas (MEC), as well as in benign Warthin's tumors (WATs). The fusion, which results from a t(11;19)(q21-22;p13) translocation, creates a chimeric gene in which exon 1 of a novel gene of unknown function, designated WAMTP1, is linked to exons 2-5 of the recently identified Mastermind-like Notch coactivator MAML2. In the fusion protein, the N-terminal basic domain of MAML2, which is required for binding to intracellular Notch (Notch ICD), is replaced by an unrelated N-terminal sequence from WAMTP1. Mutation analysis of the N-terminus of WAMTP1-MAML2 identified two regions of importance for nuclear localization (amino acids 11-20) and for colocalization with MAML2 and Notch1 ICD in nuclear granules (amino acids 21-42). Analyses of the Notch target genes HES5 and MASH1 in MEC tumors with and without the WAMTP1-MAML2 fusion revealed upregulation of HES5 and downregulation of MASH1 in fusion positive MECs compared to normal salivary gland tissue and MECs lacking the fusion. These findings suggest that altered Notch signaling plays an important role in the genesis of benign and malignant neoplasms of salivary and bronchial gland origin.

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