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J. Biol. Chem., Vol. 281, Issue 26, 18246-18256, June 30, 2006

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The Estrogen-responsive B Box Protein Is a Novel Regulator of the Retinoid Signal^*

Belamy B. Cheung, Jessica Bell, Anna Raif, Andrew Bohlken, Joanne Yan, Ben Roediger, Anne Poljak^¶, Stewart Smith, Michelle Lee, Wayne D. Thomas, Maria Kavallaris, Murray Norris, Michelle Haber, Hsiao-Lai Liu^||, Deborah Zajchowski^||, and Glenn M. Marshall^**1

From the Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales 2031, Australia, the Department of Medicine, University of Sydney, New South Wales 2006, Australia, ^¶Bioanalytical Mass Spectrometry Facility, University of New South Wales, New South Wales 2031, Australia, the ^||Department of Cancer, Berlex Biosciences, Richmond, California 94804, the ^**Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, Randwick, New South Wales 2031, Australia

Retinoic acid (RA) induces growth arrest, cell death, and differentiation in many human cancer cells in vitro and has entered routine clinical use for the treatment of several human cancer types. One mechanism by which cancer cells evade retinoid-induced effects is through repression of retinoic acid receptor (RAR) gene transcription. The RA response element (RARE) is the essential DNA sequence required for retinoid-induced RAR transcription. Here we show that the estrogen-responsive B box protein (EBBP), a member of the RING-B box-coiled-coil protein family, is a RARE-binding protein. EBBP undergoes serine threonine phosphorylation and enhanced protein stability after RA treatment. Following RA treatment, we also observed increased nuclear EBBP levels in aggregates with the promyelocytic leukemia protein at promyelocytic leukemia nuclear bodies. EBBP enhanced RA-responsive RAR transcription in RA-sensitive and -resistant cancer cells, which were resistant to both a histone deacetylase inhibitor and a demethylating agent. EBBP-specific small interfering RNA reduced basal and RA-induced RAR expression. EBBP increased RARE-transactivating function through its coiled-coil domain. Taken together, our work suggests that EBBP may have a pivotal role in the retinoid anti-cancer signal.

Received for publication, January 30, 2006 , and in revised form, April 3, 2006.

^* This work was supported by grants from the National Health and Medical Research Council Australia, the New South Wales State Cancer Council, and the Children's Cancer Institute Australia Foundation. 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 To whom correspondence should be addressed: Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, Randwick, NSW, 2031, Australia. Tel.: 61-2-9382-1721; Fax: 61-2-9382-1789; E-mail: g.marshall{at}unsw.edu.au.

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