Activation of Caspases via the Mitochondrial Pathway in Hepatocyte Apoptosis -Roles of IAPs and Smac-
| Project/Area Number |
14570503
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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 | Saitama Medical School |
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Principal Investigator |
NAGOSHI Sumiko Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saitama Medical School, Associate Professor, 医学部, 助教授 (50306271)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHIMOTO Takayuki Tokyo Medical University, Intractable Disease Research Center, Associate Professor, 医学部, 助教授 (80202406)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2002: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | apoptosis / IAP(inhibitor of apoptosis protein) / TNF-α / Smac(second mitochondria-derived activator of caspase) / hepatocyte / TNF / Smac(second mitochondria-derived activator of caspases) |
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| Research Abstract |
Activation of caspase cascade via cytochrome c released from the mitochondria is a central event in hepatocyte apoptosis. Inhibitor of apoptosis proteins (IAPs) including XIAP, IAP-1 and IAP-2, are the family proteins which suppress apoptosis by blocking caspase activation. Second mitochondria-derived activator of caspase (Smac), a mitochondrial protein released into the cytosol in response to apoptotic stimuli, was reported to inhibit this apoptosis by binding to IAPs.
TNF-α can induce apoptosis through activation of caspase cascade, but this apoptosis is inhibited by NFγB, a transcriptional factor activated by TNF-α. These IAPs are induced by activated NFκB in various cells. Previously, we demonstrated that hepatic mRNA expressions of IAP-1 and IAP-2 were increased after TNF-α treatment, causing no liver injury in mice, but pretreatment with d-galactosamine, a transcription inhibitor, reduced the peak levels of IAP-1 and IAP-2 expressions to the control levels after TNF-α administration, resulting in massive liver necrosis with hepatocyte apoptosis.
Presently we studied the roles of IAPs and Smac in hepatocyte apoptosis via caspase activation using a mouse hepatocyte cell line.
IAP-1 and IAP-2 mRNA expressions were increased from 3 to 8 hr after addition of TNF-α to the medium, whereas XIAP expression was increased from 5 to 8 hr. These increases were dose-dependent. When actinomycin D, a transcription inhibitor, was added before TNF-α addition, both levels of mRNAs and proteins of the three IAPs were lower than the control levels at 12 and 24 hr after TNF-α addition, respectively. Caspase 3 activity was gradually increased from 6 hr, but this increase was not seen after addition of TNF-α alone.
Caspase 3 activity was significantly increased 12 hr after TNF-α addition compared to the controls in cells transfected with Smac.
We conclude that decreased expressions of IAPs may be responsible for hepatocyte apoptosis via caspase activation.
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Report
(3 results)
Research Products
(3 results)
