Differential Inhibition of Smad6 and Smad7 on Bone Morphogenetic Protein- and Activin-mediated Growth Arrest and Apoptosis in B Cells*
- Akira Ishisaki‡,
- Kenji Yamato§,
- Shinichi Hashimoto‡¶,
- Atsuhito Nakao‖,
- Kiyoshi Tamaki**,
- Koji Nonaka‡,
- Peter ten Dijke**,
- Hiromu Sugino‡ and
- Tatsuji Nishiharaत
- From the ‡Department of Oral Science, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan, the §Department of Molecular Cellular Oncology/Microbiology and the ¶First Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan, the‖Department of Medicine, Chiba University, School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-0856, Japan, the‡Institute for Enzyme Research, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770, Japan, and the**Ludwig Institute for Cancer Research, Box 595, Biomedical Center, S-751 24 Uppsala, Sweden
Abstract
Smad6 and Smad7 prevent ligand-induced activation of signal-transducing Smad proteins in the transforming growth factor-β family. Here we demonstrate that both Smad6 and Smad7 are human bone morphogenetic protein-2 (hBMP-2)-inducible antagonists of hBMP-2-induced growth arrest and apoptosis in mouse B cell hybridoma HS-72 cells. Moreover, we confirmed that the ectopic expressions of Smad6 and Smad7 inhibited the hBMP-2-induced Smad1/Smad5 phosphorylation. We previously reported that Smad7 is an activin A-inducible antagonist of activin A-induced growth arrest and apoptosis in HS-72 cells. Interestingly, although mRNA expression of Smad6 was induced by activin A in HS-72 cells, Smad6 showed no antagonistic effect on activin A-induced growth arrest and apoptosis. Moreover, we found that the ectopic expression of Smad7, but not Smad6, inhibited the activin A-induced Smad2 phosphorylation in HS-72 cells. Thus, Smad6 and Smad7 exhibit differential inhibitory effects in bone morphogenetic protein-2- and activin A-mediated signaling in B lineage cells.
Footnotes
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↵* This work was supported in part by a grant from the Japan Health Science Foundation and by grants-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan.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.
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↵§§ To whom correspondence should be addressed: Dept. of Oral Science, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. Tel.: 81-3-5285-1111 (ext. 2220); Fax: 81-3-5285-1172; E-mail: tatsujin{at}nih.go.jp.
- Abbreviations:
- TGF-β
-
transforming growth factor-β
- BMP
-
bone morphogenetic protein
- hBMP-2
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human bone morphogenetic protein-2
- MTT
-
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- Rb
-
retinoblastoma protein
- pRb
-
hypophosphorylated retinoblastoma protein
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- Received December 4, 1998.
- Revision received January 28, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
