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Molecular and Cellular Biology, March 2002, p. 1369-1378, Vol. 22, No. 5
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.5.1369-1378.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Transforming Growth Factor ß1 Induces Apoptosis through Cleavage of BAD in a Smad3-Dependent Mechanism in FaO Hepatoma Cells

Byung-Chul Kim,1 Mizuko Mamura,1 Kyeong Sook Choi,2 Bruno Calabretta,3 and Seong-Jin Kim1*

Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892-50551,1 Laboratory of Endocrinology and Laboratory of Medical Genetics, Institute for Medical Sciences, Ajou University School of Medicine, Paldal-Gu, Suwon, Korea ,2 Department of Microbiology/Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 191073

Received 6 September 2001/ Returned for modification 19 October 2001/ Accepted 29 November 2001

Transforming growth factor ß (TGF-ß) induces apoptosis in a variety of cells. We have previously shown that TGF-ß1 rapidly induces apoptosis in the FaO rat hepatoma cell line. We have now studied the effect of TGF-ß1 on the expression of different members of the Bcl-2 family in these cells. We observed no detectable changes in the steady-state levels of Bcl-2, Bcl-XL, and Bax. However, TGF-ß1 induced caspase-dependent cleavage of BAD at its N terminus to generate a 15-kDa truncated protein. Overexpression of the 15-kDa truncated BAD protein enhanced TGF-ß1-induced apoptosis, whereas a mutant BAD resistant to caspase 3 cleavage blocked TGF-ß1-induced apoptosis. Overexpression of Smad3 dramatically enhanced TGF-ß1-induced cleavage of BAD and apoptosis, whereas antisense Smad3 blocked TGF-ß1-induced apoptosis and BAD cleavage. These results suggest that TGF-ß1 induces apoptosis through the cleavage of BAD in a Smad3-dependent mechanism.

* Corresponding author. Mailing address: Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Building 41, Room B1106, Bethesda, MD 20892-5055. Phone: (301) 496-8350. Fax: (301) 496-8395. E-mail: Kims{at}mail.nih.gov.

Molecular and Cellular Biology, March 2002, p. 1369-1378, Vol. 22, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.5.1369-1378.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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