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This version published online on December 18, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0105
Molecular Endocrinology Vol. 0, No. 2003 200301051-
doi:10.1210/me.2003-0105
Copyright © 2003 by the Endocrine Society.
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Submitted on March 26, 2003
Accepted on December 10, 2003

Fos and Jun Inhibit Estrogen-Induced Transcription of the Human Progesterone Receptor Gene Through an Activator Protein-1 Site

Larry N. Petz1, Yvonne S. Ziegler1, Jennifer R. Schultz1, and Ann M. Nardulli1*

1 Department of Molecular and Integrative Physiology; University of Illinois, Urbana, Illinois 61801

* To whom correspondence should be addressed. E-mail: anardull{at}life.uiuc.edu.

The progesterone receptor (PR) gene is activated by estrogen in normal reproductive tissues and in MCF-7 human breast cancer cells. Although it is typically thought that estrogen-responsiveness is mediated through estrogen response elements (EREs), the human PR gene lacks a palindromic ERE sequence. We have identified an activating protein-1 (AP-1) site at +745 in the human PR gene that bound purified Fos and Jun and formed a complex with Fos/Jun heterodimers present in MCF-7 nuclear extracts. Surprisingly, mutating the +745 AP-1 site in the context of a 1.5 kb region of the PR gene significantly enhanced estrogen receptor (ER) {alpha}-mediated transactivation suggesting that the wild type +745 AP-1 site plays a role in inhibiting PR gene expression in the presence of hormone. In support of this idea transient transfection assays demonstrated that increasing levels of Fos and Jun repressed transcription of a reporter plasmid containing the +745 AP-1 site. Fos levels were transiently increased, ER{alpha} levels were decreased, and Jun was dephosphorylated after MCF-7 cells were treated with estrogen. Chromatin immunoprecipitation assays demonstrated that Jun was associated with the +745 AP-1 site in the endogenous PR gene in the presence and in the absence of estrogen, but that ER{alpha} and Fos were only associated with the +745 AP-1 site after estrogen treatment of MCF-7 cells. Our studies suggest that the human PR gene is regulated by multiple transcription factors and that the differential binding of these dynamically-regulated trans acting factors influences gene expression.
Key words: progesterone receptor • AP-1 • estrogen receptor • gene expression • transcription

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  PR
Ligands:   17β-Estradiol



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