Induction of programmed death of tumor cells by activation of betal integrin.
| Project/Area Number |
17590074
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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 |
Biological pharmacy
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| Research Institution | Tokyo University of Science |
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Principal Investigator |
FUKAI Fumio Tokyo University of Science, Faculty of Pharmaceutical Science, Professor, 薬学部, 教授 (90124487)
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| Co-Investigator(Kenkyū-buntansha) |
KODAMA Hiroaki Tokyo University of Science, Faculty of Science and Engineering, Assistant Professor, 理工学部, 教授 (80205418)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2005: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | Fibronectin / Tenascin / Integrin / Adhesion / Programmed cell death / Apoptosis / Ras / MAPK / MAPキナーゼ / G2 / M / 悪性腫瘍 / シンデカン / MAP-Kinase pathway |
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| Research Abstract |
Molecular mechanism by which TNIII induces programmed death of tumor cells through stimulating β1 integrin activation was investigated. TNIII-induced activation of βl integrins induced dephosphorylation of FAK (Tyr397), FAK (Tyr 925), Src (Tyr 397) and Akt, resulting in caspase-independent apoptotic death of WI38VA13 fibrosarcoma-like cells. This apoptosis was accompanied by the nuclear translocation of AIF that is known to be implicated in caspase-independent apoptosis. Additionally, TNIII stimulated Rac activation and subsequent generation of reactive oxygen spices (ROS), suggesting the involvement of ROS in the TNIII-induced apoptotic cell death.
Interestingly, TNIII-induced response of normal fibroblasts was clearly distinct from that of tumor cells. TNIII completely rescued mormal fibroblasts NIH3T3 from the serum-deprived apoptosis, in which Ras in a resting state was activated. In sharp contrast, TNIII elicited apoptotic death against fibrosarcoma-like WI38VA13 cells, in which Ras in a constitutively active state was transiently inactivated. To explain this difference in cellular response to TNIII, NIH3T3 cells stably expressing constitutively active mutant of Ras (NIH-V7) were constructed. When NIH-V7 cells were incubated with TNIII, the cells underwent programmed death in concomitant with a transient inactivation of Ras.
Thus, TNIII appears to have the ability to control cell survival/apoptosis by stimulating Ras activation, in which the activation status of Ras may be an important determinant whether cells survive or undergo apoptosis.
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Report
(3 results)
Research Products
(24 results)
