title: Kit K641E oncogene up-regulates Sprouty homolog 4 and trophoblast glycoprotein in interstitial cells of Cajal in a murine model of gastrointestinal stromal tumours.
abstract: Gastrointestinal stromal tumours (GIST) are thought to derive from the interstitial cells of Cajal (ICC) or an ICC precursor. Oncogenic mutations of the receptor tyrosine kinase KIT are present in most GIST. KIT K642E was originally identified in sporadic GIST and later found in the germ line of a familial GIST cohort. A mouse model harbouring a germline Kit K641E mutant was created to model familial GIST. The expression profile was investigated in the gastric antrum of the Kit(K641E) murine GIST model by microarray, quantitative PCR and immunofluorescence. Gja1/Cx43, Gpc6, Gpr133, Pacrg, Pde3a, Prkar2b, Prkcq/Pkce, Rasd2, Spry4 and Tpbg/5T4 were found to be up-regulated. The proteins encoded by Gja1/Cx43, Pde3a, Prkcq/Pkce were localized in Kit-ir ICC in wild-type and Kit(K641E) animals while Spry4 and Tpbg/5T4 were detected in Kit-ir cells only in Kit(K641E), but not in Kit(WT/WT) animals. Most up-regulated genes in this mouse model belong to the gene expression profile of human GIST but also to the profile of normal Kit(+) ICC in the mouse small intestine. Spry4 and Tpbg/5T4 may represent candidates for targeted therapeutic approaches in GIST with oncogenic KIT mutations.
authors.affiliation: Laboratory of Neurophysiology, Faculty of Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: Gromova
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ralea
authors.forename: Anne
authors.initials: A
authors.lastname: Lefort
authors.forename: Frédérick
authors.initials: F
authors.lastname: Libert
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.forename: Christophe
authors.initials: C
authors.lastname: Erneux
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Vanderwinden
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D046152:Gastrointestinal Stromal Tumors / Q000201:enzymology / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056885:Interstitial Cells of Cajal / Q000201:enzymology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C499037:Spry4 protein, mouse; D019009:Proto-Oncogene Proteins c-kit