2001 Fiscal Year Final Research Report Summary
A study on an immunosuppressant mizoribine-binding renal proteins (esp. molecular chaperones)
| Project/Area Number |
11671024
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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 |
Kidney internal medicine
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| Research Institution | Akita University |
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Principal Investigator |
WAKUI Hideki Akita University, School of Medicine, Lecture, 医学部, 講師 (70240463)
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| Co-Investigator(Kenkyū-buntansha) |
KOMATSUDA Atsushi Akita University, School of Medicine, Research Associate, 医学部, 助手 (70272044)
ITOH Hideaki Akita University, School of Medicine, Associate Professor, 医学部, 助教授 (80168369)
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| Project Period (FY) |
1999 – 2001
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| Keywords | Immunosuppressant / Mizonbine / Molecular chaperone / HSP60 / 14-3-3 proteins / RIP140 |
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| Research Abstract |
1. Mammalian HSP60 is a major target for an immunosuppressant mizoribine (Reference 1)
A 60-kDa mizoribine-binding protein was isolated from porcine kidney. Based on its amino acid sequences, the protein was identified as HSP60. Moreover, mizoribine interfered with the chaperone activity of HSP60. These findings suggest the possibility that one mechanism for the therapeutic effect of mizoribine could be to inhibit the chaperone activity of HSP60.
2. Functional interaction of the immunosuppressant mizoribine with the 14-3-3 protein (Reference 2)
Four 30-32 kDa mizoribine-binding proteins were isolated from porcine kidney. Based on their amino acid sequences, the. proteins were identified as 14-3-3 protein isoforms, which have recently been considered to be molecular chaperones. Mizoribine affected the conformation of 1 4-3-3 proteins and enhanced the glucocorticoid receptor (GR)/14-3-3 protein interaction. Mizoribine also had a stimulatory effect on transcriptional activation by the GR. These results point to the possibility that one mechanism for the therapeutic effect of mizoribine could be to regulate the GR function via 14-3-3 proteins.
3. Regulation of glucocorticoid receptor activity by 14-3-3-dependent intracellular relocalization of the corepressor RIP140 (Reference 3)
The function of 14-3-3 proteins, which were identified as mizoribine-binding proteins in Reference 2, was further elucidated. 14-3-3 proteins interacted with the nuclear receptor corepressor RIP140 and changed its subcellular localization. These results suggest that the positive effect of 14-3-3 on glucocorticoid receptor transactivation is due to 14-3-3 binding to RIP140 and removing the negatively acting RIP140 from the nucleus. Moreover, 14-3-3 proteins could bind to various other nuclear receptors and co factors. This indicates a more general role for 14-3-3 proteins in the signal transduction systems.
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