1999 Fiscal Year Final Research Report Summary
Role of gain-of-function mutations of c-kit gene on tumor development in gastrointestinal stromal tumor.
| Project/Area Number |
10670471
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Osaka University |
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Principal Investigator |
SHINOMURA Yasuhisa Osaka University Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (90162619)
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| Co-Investigator(Kenkyū-buntansha) |
TSUTSUI Shusaku Osaka University Hospital, Medical Stuff, 医学部・附属病院, 医員
KANAYAMA Shuji Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (40185913)
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| Project Period (FY) |
1998 – 1999
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| Keywords | GIST / c-kit / stromal tumor / mutation |
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| Research Abstract |
The c-kit proto-oncogene encodes a receptor tyrosine kinase (KIT), the ligand of which is stem cell factor (SCF). KIT consists of an extracellular domain, a transmembrane domain, a juxtamembrane domain and a tyrosine kinase domain. Gain-of-function mutations of the c-kit gene have been found in several tumor mast cell lines of rodents and humans and in mast cell tumors of humans. The constitutive activation of KIT in these cell lines and tumors was the result of a point mutation in the tyrosine kinase domain of the c-kit gene.
A large proportion of mesenchymal tumors, which do not show typical features of smooth muscle cells or Schwann cells, are presently designated as gastrointestinal stromal tumor (GIST). We found that most of GISTs expressed KIT. Sequencing of c-kit complementary DNA from GISTs revealed a variety of mutations in the region between the transmembrane and tyrosine kinase domains. Most of mutations in GISTs were located with in the 11 amino acids (Lys-550 to Val-560) in the juxtamembrane domain. The corresponding mutant KIT proteins were constitutively dimerized and activated without the KIT ligands. Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells. Most of all GISTs which developed during a short periods showed mutations of c-kit, while half of mutations of c-kit contribute to tumor development in GIST.
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[Publications] H. Ueyama, T. Kiyohara, N. Sawada, K. Isozaki, S. Kitamura, S. Kondo, J. Miyagawa, S. Kanayama, Y. Shinomura, H. Ishikawa, T. Ohtani, R. Nezu, S. Nagata, Y. Matsuzawa: "High Fas ligand expression on lymphocytes in lesions of ulcerative colitis."Gut. 43(1). 48-55 (1998)
Description
「研究成果報告書概要(欧文)」より
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