2002 Fiscal Year Final Research Report Summary
The mechanism of cell death induced by hepatitis B virus X protein
| Project/Area Number |
12672142
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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 | Japanese Foundation for Cancer Research |
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Principal Investigator |
SHIRAKATA Yumiko The Cancer Inst., JFCR Dept. Gene Res., 癌研究所・遺伝子研究施設部, 研究員 (60179041)
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| Co-Investigator(Kenkyū-buntansha) |
KOIKE Katsuro The Cancer Inst., JFCR Dept. Gene Res., 癌研究所・遺伝子研究施設部, 部長 (30085625)
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| Project Period (FY) |
2000 – 2002
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| Keywords | hepatitis B virus / X gene / cell death / mitochondria / mitochondrial membrane potential / ROS |
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| Research Abstract |
The hepatitis B virus X protein (HBx) has been implicated in the carcinogenicity of this virus as a causative factor by means of its transactivation function in development of hepatocellular carcinoma (HCC). However, we and others have recently reported that HBx is located in mitochondria and causes subsequent cell death. In this study, we therefore examined the mechanism of HBx-related cell death. Using EGFP-fusion constructs of HBx, the region required for its mitochondrial localization was mapped to amino acid (aa) 68 to 117, which is essential for cell death but inactive for transactivation function. In vitro binding analysis supported a notion that the recombinant HBx associates with isolated mitochondria through the region of aa 68 to 117, without causing redistribution of cytochrome c and apoptosis inducing factor (AIF). A cytochemical analysis revealed that mitochondrial membrane potential was decreased by HBx association with mitochondria, suggesting that HBx induces dysfunction of permeability transition pore (PTP) complex. Furthermore, PTP inhibitors, reactive oxygen species (ROS) scavengers and Bcl-x_L, which are known to stabilize mitochondrial membrane potential, prevented HBx-induced cell death. Collectively, the present results suggest that location of HBx in mitochondria of HBV-infected cells causes loss of mitochondtial membrane potential and subsequently induces mitochondria-dependent cell death.
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