2000 Fiscal Year Final Research Report Summary
FOCAL ADHESION KINASE AS A POTENTIAL TARGET FOR THE THERAPY OF THE HUMAN GLIOMA THE HUMAN GLIOMA
| Project/Area Number |
11672275
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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 |
応用薬理学・医療系薬学
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| Research Institution | KYORITSU COLLEGE OF PHARMACY |
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Principal Investigator |
SONODA Yoshiko KYORITSU COLLEGE OF PHARMACY, OF BIOCHEMISTRY, ASSOCIATE PROFESSOR (30050743)
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| Co-Investigator(Kenkyū-buntansha) |
KASAHARA Tadashi KYORITSU COLLEGE OF PHARMACY OF BIOCHEMISTRY, 薬学部, PROFESSOR (60049096)
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| Project Period (FY) |
1999 – 2000
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| Keywords | FAK / PI3-kinase / Akt / survival / glioma / apoptosis / IAP / NF-kB |
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| Research Abstract |
We found that focal adhesion kinase (FAK) was tyrosine-phosphorylated by oxidative stress before apoptosis occurred (Biochem. Biophys. Res. Commun., 1997). Further, PKB/Akt which has been implicated in the pathway of survival signal was serine phosphorylated following tyrosine-phosphorylation of FAK, therefore, proposing FAK antiapoptotic role in oxidative stress-induced apoptosis in a human glioblastoma cell line, T98G (J. Biol. Chem. 1999). To clarify the role of FAK in apoptosis, we established FAK-overexpressed HL-60 cells and confirmed that FAK-transfected HL-60 (HL-60/FAK) cells were highly resistant to hydrogen peroxide (1mM) and etoposide (50μg/mL)-induced apoptosis compared to the vector-transfected cells (J. Biol. Chem. 2000). HL-60/FAK exhibited significant activation of NF-kB and induction of inhibitor-of-apoptosis proteins (IAPs). Mutagenesis of FAK revealed that Y397 and Y925, both of which are involved in the tyrosine-phosphorylation sites, are prerequisites for the antiapoptotic activity as well as induction of IAPs. The mutated FAK (Y397F-FAK, 397FAK) lost anti-apoptotic function. As the mutated FAK, 397FAK, might function as a dominant negative FAK, we therefore evaluated the mutated FAK as proapoptotic. We introduced 397FAK gene to human glioma cells, T98G using an adenoviral vector (Adv). 397FAK induced FAK degradation and apoptosis in T98G cells. Furthermore, co-transfection of 397FAK with N-terminal deleted IkBalpha (IkBdN) which is super suppressor of NF-kB, enhanced apoptosis.
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Research Products
(8 results)
