Smad7 Is an Activin-inducible Inhibitor of Activin-induced Growth Arrest and Apoptosis in Mouse B Cells

doi:10.1074/jbc.273.38.24293

Smad7 Is an Activin-inducible Inhibitor of Activin-induced Growth Arrest and Apoptosis in Mouse B Cells*

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, 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, and the ^‖Ludwig Institute for Cancer Research, Box 595, Biomedical Center, S-751 24 Uppsala, Sweden

Abstract

Members of the transforming growth factor-β (TGF-β) family, which includes the activins, relay signals from serine/threonine kinase receptors in membrane to nucleus via intracellular Sma- and Mad-related (Smad) proteins. Inhibitory Smad proteins were found to prevent the interaction between the serine/threonine kinase receptors and pathway-restricted Smad proteins. Smad7 was identified as a TGF-β-inducible antagonist of TGF-β signaling, and it may participate in a negative feedback loop to control TGF-β signaling. Here we demonstrate that the mRNA expression of Smad7 is induced by activin A in mouse B cell hybridoma HS-72 cells, which undergo growth arrest and apoptosis upon exposure to activin A. The ectopic expression of mouse Smad7 in HS-72 cells suppressed the activin A-induced cell cycle arrest in the G₁ phase by abolishing the activin A-induced expression of p21^CIP1/WAF1 and hypophosphorylation of retinoblastoma protein. Furthermore, Smad7 expression suppressed activin A-induced apoptosis in HS-72 cells. Thus, our data indicate that Smad7 is an activin A-inducible antagonist of activin A-induced growth arrest and apoptosis of B lineage cells.

Footnotes

↵* This work was supported in part by grants-in-aid from the Ministry of Education, Science, and Culture of Japan and from the Ministry of Health and Welfare 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.
↵** 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.
↵2 M. Afrakhte, unpublished results.
Abbreviations:

TGF-β

transforming growth factor-β

Smad

Sma- and Mad-related

ActR

activin receptor

hBMP

human bone morphogenic protein

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

Rb

retinoblastoma protein

GAPDH

glyceraldehyde 3-phosphate dehydrogenase

TβR

TGF-β receptor

CDK

cyclin-dependent kinase

pRB

hypophosphorylated Rb

ppRb

hyperphosphorylated Rb.
- Received April 10, 1998.
- Revision received June 30, 1998.
The American Society for Biochemistry and Molecular Biology, Inc.