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J. Biol. Chem., Vol. 281, Issue 39, 28596-28604, September 29, 2006

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Estrogen Receptor Isoform-specific Regulation of the Retinoblastoma-binding Protein 1 (RBBP1) Gene

ROLES OF AF1 AND ENHANCER ELEMENTS^*

David G. Monroe¹, Frank J. Secreto, John R. Hawse, Malayannan Subramaniam, Sundeep Khosla, and Thomas C. Spelsberg

From the Department of Biochemistry and Molecular Biology and the Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

Estrogen (E2) is involved in mediating many important functions relevant to osteoblast biology through the actions of the estrogen receptors (ER) and . To further understand the mechanisms of ER-specific regulation, we used microarray and reverse transcription-PCR analyses of E2-treated U2OS-ER or -ER cells and identified retinoblastoma-binding protein 1 (RBBP1) as a major E2-regulated gene. RBBP1 is a retinoblastoma cofactor involved in the control of osteoblastic proliferation. Although RBBP1 mRNA levels rapidly increased after 2 h of E2 treatment in both U2OS-ER-expressing lines, a sustained induction was only observed in U2OS-ER cells. Examination of the RBBP1 genomic sequence revealed an ER response element and a Sp1 site located within the first intron. Chromatin immunoprecipitation analyses demonstrated that E2-dependent ER binding to the intron 1 enhancer region was constitutive, whereas ER binding was transient, consistent with the mRNA time course. Interestingly, transient transfection and receptor mutational studies revealed that RBBP1 induction by ER only requires the Sp1 site, whereas ER utilizes both the Sp1 and estrogen response elements binding sites for maximal E2-dependent activation. Stable U2OS transfectants containing a deletion of the ER activation function 1 (AF1) resulted in a temporal mRNA induction profile similar to that of wild type ER. Further, overexpression and chromatin immunoprecipitation analyses also demonstrated that E2-dependent RBBP1 induction is SRC2-dependent for both ER isoforms. These results describe an E2-dependent, ER isoform-specific transcriptional activation of the RBBP1 gene, which in part, is explained by the differential activity of ER AF1 and enhancer element binding.

Received for publication, May 31, 2006 , and in revised form, July 26, 2006.

^* This work was supported by National Institutes of Health Grant PO1-AG04875-21 and by grants from the Breast Cancer Research Foundation (New York) and the Mayo 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: Dept. of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 1601C Guggenheim, 200 1^st St. S.W., Rochester, MN 55905. Tel.: 507-284-1926; Fax: 507-284-2053; E-mail: Monroe.David{at}mayo.edu.

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