1996 Fiscal Year Final Research Report Summary
Tumor suppression by using gelsolin mutants
| Project/Area Number |
07457546
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | Hokkaido University |
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Principal Investigator |
KUZUMAKI Noboru School of Medicine, Hokkaido University Professor, 医学部, 教授 (80091445)
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| Co-Investigator(Kenkyū-buntansha) |
FUJITA Hisakazu School of Medicine, Hokkaido University Instructor, 医学部, 助手 (30212187)
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| Project Period (FY) |
1995 – 1996
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| Keywords | gelsolin / mutant / tumor suppression / human cancers |
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| Research Abstract |
1. A mutant gelsolin, [His321] gelsolin, was isolated from R1, a flat revertant of human activated c-Ha-ras oncogene-transformed NIH/3T3 cells (EJ-NIH/3T3). [His321] Gelsolin has a histidine instead of a proline residue at position 321 and suppresses the tumorigenicity of EJ-NHI/3T3 cells when it is constitutively expressed. [His321] Gelsolin has decreased actin-filament-severing activity and increased nucleating activity compared with wild-type gelsolin in vitro. [His321] gelsolin inhibits PtdInsP2 hydrolysis by phospholipase C gamma 1 more strongly than wild-type gelsolin in vitro because of its higher binding capacity for phosphoinositol lipid. Our results suggest that the segment S3 which contains the mutation is functionally relevant for regulation of gelsolin's activities even though the relevant actin-binding domains are in segments 1,2, and 4-6, and that the region around the residue 321 may contain a phosphoinositol-lipid-binding site. Altered functions of [His321] gelsolin mi
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ght be important for the loss of tumorigenicity of the ras-transformed cells.
2. We examined the expression of gelsolin in a number of human bladder cancer cell lines and tissues. In all 6 cell lines and in 14 of the 18 tumor tissues (77.8%), gelsolin expression was undetectable or extremely low in comparison with its expression in normal bladder epithelial cells. Furthermore, upon the introduction of the exogenous human or mouse authentic gelsolin cDNA into a human bladder cancer cell line, UMUC-2, gelsolin transfectants of UMUC-2 greatly reduced the colony-forming ability and the tumorigenicity in vivo. These results suggest that gelsolin plays a key role as a tumor suppressor in human urinary bladder carcinogenesis.
3. Stimulation by PDGF or EGF induced far less DNA synthesis in two NIH/3T3 clones expressing His321 that in two clones transfected with the vector alone. These results suggest that through the effects on the signal transduction pathway of PDGF and/or EGF His321-mutated gelsolin inhibits the growth of NIH/3T3. Less
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