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Hirota, S, Isozaki, K, Moriyama, Y, Hashimoto, K, Nishida, T, Ishiguro, S, Kawano, K, Hanada, M, Kurata, A, Takeda, M, Muhammad Tunio, G, Matsuzawa, Y, Kanakura, Y, Shinomura, Y and Kitamura, Y (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577-80


Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.




Amino Acid Sequence; Animals; Antigens, CD34/analysis; Cell Line; Cell Transformation, Neoplastic; DNA, Complementary; Digestive System/cytology; Esophageal Neoplasms/genetics; Esophageal Neoplasms/metabolism; Esophageal Neoplasms/pathology; Gastrointestinal Neoplasms/chemistry; Gastrointestinal Neoplasms/genetics; Gastrointestinal Neoplasms/pathology; Humans; Intestinal Neoplasms/chemistry; Intestinal Neoplasms/genetics; Intestinal Neoplasms/pathology; Ligands; Mice; Mice, Nude; Molecular Sequence Data; Mutation; Phosphorylation; Phosphotyrosine/metabolism; Proto-Oncogene Proteins c-kit/analysis; Proto-Oncogene Proteins c-kit/chemistry; Proto-Oncogene Proteins c-kit/genetics; Proto-Oncogene Proteins c-kit/metabolism; Recombinant Proteins/pharmacology; Sequence Deletion; Stem Cell Factor/pharmacology; Stomach Neoplasms/genetics; Stomach Neoplasms/metabolism; Stomach Neoplasms/pathology; Transfection



Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

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