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Originally published In Press as doi:10.1074/jbc.M212098200 on April 2, 2003

J. Biol. Chem., Vol. 278, Issue 24, 21474-21482, June 13, 2003
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Selective Interactions of Krüppel-like Factor 9/Basic Transcription Element-binding Protein with Progesterone Receptor Isoforms A and B Determine Transcriptional Activity of Progesterone-responsive Genes in Endometrial Epithelial Cells*

Xue-Lian Zhang {ddagger}, Daying Zhang {ddagger}, Frank J. Michel {ddagger}, Jason L. Blum {ddagger}, Frank A. Simmen {ddagger} § and Rosalia C. M. Simmen {ddagger} § ¶

From the {ddagger} Interdisciplinary Concentration in Animal Molecular and Cell Biology, University of Florida, Gainesville, Florida 32611-0910, § Arkansas Children's Nutrition Center and the Department of Physiology & Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202

The Sp/KLF transcription factor basic transcription element-binding protein (BTEB1) regulates gene transcription by binding to GC-rich sequence motifs present in the promoters of numerous tissue-specific as well as housekeeping genes. Similar to other members of this family, BTEB1 can act as a transactivator or transrepressor depending on cell and promoter context, although the molecular mechanism underlying these distinct activities remains unclear. Here we report that BTEB1 can mediate signaling pathways involving the nuclear receptor for the steroid hormone progesterone in endometrial epithelial cells by its selective interaction with the progesterone receptor (PR) isoforms, PR-A and PR-B. Functional interaction with ligand-activated PR-B resulted in superactivation of PR-B transactivity, facilitated the recruitment of the transcriptional integrator CREB-binding protein within the PR-dimer, and was dependent on the structure of the ligand bound by PR-B. By contrast, BTEB1 did not influence agonist-bound PR-A transactivity, although it augmented PR-A inhibition of PR-B-mediated transactivation as well as potentiated ligand-independent PR-A transcriptional activity in the presence of CREB-binding protein. We also demonstrate similar positive modulatory actions of BTEB1-related family members Krüppel-like family (KLF) 13/FKLF2/BTEB3 and Sp1 on PR-B transactivity. Further, we provide support for the potential significance of the selective functional interactions of PR isoforms with BTEB1 in the peri-implantation uterus using mouse and pig models and in the breast cancer cell lines MCF-7 and T47D. Our results suggest a novel mechanism for the divergent physiological consequences of PR-A and PR-B on progesterone-dependent gene transcription in the uterus involving select KLF members.


Received for publication, November 27, 2002 , and in revised form, March 10, 2003.

* This work was supported in part by the National Institutes of Health Grant HD21961 and USDA-CRIS-6251-5100-002-06S. 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.

To whom correspondence should be addressed. Tel.: 501-364-2849; Fax: 501-364-3161; E-mail: simmenrosalia{at}uams.edu.


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