Filamin A-Bound PEBP2β/CBFβ Is Retained in the Cytoplasm and Prevented from Functioning as a Partner of the Runx1 Transcription Factor

Abstract

The heterodimeric transcription factor PEBP2/CBF is composed of a DNA-binding subunit, called Runx1, and a non-DNA-binding subunit, called PEBP2β/CBFβ. The Runx1 protein is detected exclusively in the nuclei of most cells and tissues, whereas PEBP2β is located in the cytoplasm. We addressed the mechanism by which PEBP2β localizes to the cytoplasm and found that it is associated with filamin A, an actin-binding protein. Filamin A retains PEBP2β in the cytoplasm, thereby hindering its engagement as a Runx1 partner. The interaction with filamin A is mediated by a region within PEBP2β that includes amino acid residues 68 to 93. The deletion of this region or the repression of filamin A enables PEBP2β to translocate to the nucleus. Based on these observations, we propose that PEBP2β has two distinct domains, a newly defined regulatory domain that interacts with filamin A and the previously identified Runx1-binding domain.

ACKNOWLEDGMENTS

This research was supported in part by research grants from the Ministry of Education, Science, Sports, Culture and Technology of Japan. M.S. is a member of the 21st Century COE program, “Center for Innovative Therapeutic Development Towards the Conquest of Signal Transduction Diseases,” headed by K. Sugamura at Tohoku University.

We thank M. Shiina and K. Ogata for their valuable comments on the structural aspects of PEBP2β. We also thank D. Tenen for providing the p-M-CSF-R-luc reporter construct. We are grateful to M. Kuji for secretarial assistance.