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Originally published In Press as doi:10.1074/jbc.M003292200 on September 18, 2000

J. Biol. Chem., Vol. 275, Issue 49, 38794-38801, December 8, 2000
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Overexpression of Bcl-2 Enhances LIGHT- and Interferon-gamma -mediated Apoptosis in Hep3BT2 Cells*

Mei-Chieh ChenDagger , Tsui-Ling HsuDagger , Tien-Yau Luh§, and Shie-Liang HsiehDagger ||

From the Dagger  Institute and Department of Microbiology and Immunology, National Yang-Ming University, Taipei 11221, Taiwan, the § Department of Chemistry, National Taiwan University, Taipei 11221, Taiwan, and the  Immunology Research Center, National Yang-Ming University, Taipei 11221, Taiwan

LIGHT is a member of the tumor necrosis factor superfamily and is the ligand for LT-beta R, HVEM, and decoy receptor 3. LIGHT has a cytotoxic effect, which is further enhanced by the presence of interferon-gamma (IFN-gamma ). Although LIGHT/IFN-gamma can activate caspase activity, neither benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone nor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone can completely inhibit LIGHT/IFN-gamma -mediated apoptosis. Moreover, overexpression of Bcl-2 further enhances LIGHT/IFN-gamma -mediated apoptosis. It appears that LIGHT and IFN-gamma act synergistically to activate caspase-3, with the resultant cleavage of Bcl-2, removal of the BH4 domain, leading to conversion of Bcl-2 from an antiapoptotic to a proapoptotic form in p53-deficient hepatocellular carcinoma Hep3BT2 cells. Thus, LIGHT seems to be able to override the protective effect of Bcl-2 and induce cell death. Although benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone and benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone can prevent the cleavage of Bcl-2 by LIGHT/IFN-gamma , they only partially inhibit apoptosis in Hep3BT2 cells that are overexpressing Bcl-2. In contrast, both LIGHT/IFN-gamma -mediated apoptosis and Bcl-2 cleavage are inhibited by free radical scavengers, indicating that free radicals may play an essential role in LIGHT/IFN-gamma -mediated apoptosis at a step upstream of caspase-3 activation. These results suggest that LIGHT signaling may diverge into multiple, separate processes.

* This work was supported by National Science Council, Taiwan, Grant NSC89-2320-B-010-002.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom all correspondence should be addressed: Institute of Microbiology and Immunology, National Yang-Ming University, Shih-Pai, Taipei 11221, Taiwan. Tel.: 886-2-28267161; Fax: 886-2-28212880; E-mail: slhsieh@ym.edu.tw.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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