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J. Biol. Chem., Vol. 281, Issue 28, 19092-19099, July 14, 2006

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Essential Role of KIBRA in Co-activator Function of Dynein Light Chain 1 in Mammalian Cells^*

Suresh K. Rayala¹, Petra den Hollander¹, Bramanandam Manavathi, Amjad H. Talukder, Chunying Song, Shaohua Peng, Angelika Barnekow^¶, Joachim Kremerskothen^¶, and Rakesh Kumar²

From the Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, The University of Texas Graduate School of Biomedical Sciences at Houston, Texas 77030, and ^¶Department for Experimental Tumor Biology, University Muenster, Badestrasse 9, D-48149 Muenster, Germany

Recently dynein light chain 1 (DLC1), a cytoskeleton signaling component, has been shown to interact with and transactivate estrogen receptor- (ER), leading to increased expression of ER target genes and growth stimulation of breast cancer cells. However, the molecular mechanism by which DLC1 regulates the ER pathway remains poorly understood. To gain insights into the putative mechanism, here we set out to identify novel DLC1-interacting proteins. We identified KIBRA, a WW domain- and a glutamic acid stretch-containing protein, as a DLC1-binding protein and showed that it interacts with DLC1 both in vitro and in vivo. We found that KIBRA-DLC1 complex is recruited to ER-responsive promoters. We also found that KIBRA-DLC1 interaction is mandatory for the recruitment and transactivation functions of ER or DLC1 to the target chromatin. Finally we found that KIBRA interacts with histone H3 via its glutamic acid-rich region and that such interaction might play a mechanistic role in conferring an optimal ER transactivation function as well as the proliferation of ligand-stimulated breast cancer cells. Together these findings indicate that DLC1-KIBRA interaction is essential for ER transactivation in breast cancer cells.

Received for publication, January 3, 2006 , and in revised form, April 6, 2006.

^* This study was supported by National Institutes of Health Grants CA80066 and CA65746 (to R. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. E-mail: rkumar{at}mdanderson.org.

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