Interaction and Functional Cooperation of PEBP2/CBF with Smads

doi:10.1074/jbc.274.44.31577

Interaction and Functional Cooperation of PEBP2/CBF with Smads

SYNERGISTIC INDUCTION OF THE IMMUNOGLOBULIN GERMLINE Cα PROMOTER*

From the ^‡Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 70-8455, Japan, the ^¶Department of Viral Oncology, Institute for Virus Research, Kyoto University, Shogo-in, Sakyo-ku, Kyoto 606-8507, Japan, and the ^‖Department of Molecular Genetics and Microbiology, Graduate Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0122

Abstract

Smads are signal transducers for members of the transforming growth factor-β (TGF-β) superfamily. Upon ligand stimulation, receptor-regulated Smads (R-Smads) are phosphorylated by serine/threonine kinase receptors, form complexes with common-partner Smad, and translocate into the nucleus, where they regulate the transcription of target genes together with other transcription factors. Polyomavirus enhancer binding protein 2/core binding factor (PEBP2/CBF) is a transcription factor complex composed of α and β subunits. The α subunits of PEBP2/CBF, which contain the highly conserved Runt domain, play essential roles in hematopoiesis and osteogenesis. Here we show that three mammalian α subunits of PEBP2/CBF form complexes with R-Smads that act in TGF-β/activin pathways as well as those acting in bone morphogenetic protein (BMP) pathways. Among them, PEBP2αC/CBFA3/AML2 forms a complex with Smad3 and stimulates transcription of the germline Ig Cα promoter in a cooperative manner, for which binding of both factors to their specific binding sites is essential. PEBP2 may thus be a nuclear target of TGF-β/BMP signaling.

Footnotes

↵* This work was supported by Grant-in-aid for Priority Areas on Cancer Research 09253220 (to Y. I.) and Grant-in-aid on Immune Disease Research 08282105 (to K. M.) from the Ministry of Education, Science, Sports and Culture, 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.
↵§ These two authors contributed equally to the work.

Supported by National Institutes of Health Grant RO1 AI23283.

Supported by the Research for the Future Program of the Japan Society for the Promotion of Science. To whom correspondence may be addressed. Tel. and Fax: 81-3-3918-0342; E-mail: miyazono-ind@umin.ac.jp.

To whom correspondence may also be addressed. Tel.: 81-75-751-4028; Fax: 81-75-752-3232; E-mail: yito@virus.kyoto-u.ac.jp.
↵2 Y.-W. Zhang and Y. Ito, unpublished data.
Abbreviations:

TGF-β

transforming growth factor-β

BMP

bone morphogenetic protein

R-Smad

receptor-regulated Smad

Co-Smad

common-partner Smad

PEBP2

polyomavirus enhancer binding protein 2

CBF

core binding factor

Ig Cα

immunoglobulin Cα

TβR-I

TGF-β type I receptor

BMPR-IB

BMP type IB receptor

WT

wild-type

TβRE

TGF-β-responsive element

GST

glutathione S-transferase

MH

Mad homology

EMSA

electrophoretic mobility shift assay

AD

activation domain
- Received July 12, 1999.
- Revision received August 30, 1999.
The American Society for Biochemistry and Molecular Biology, Inc.