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Molecular and Cellular Biology, August 2002, p. 5451-5466, Vol. 22, No. 15
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.15.5451-5466.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Jun Dimerization Protein 2 Functions as a Progesterone Receptor N-Terminal Domain Coactivator

Suzanne E. Wardell,1 Viroj Boonyaratanakornkit,2 James S. Adelman,2 Ami Aronheim,3 and Dean P. Edwards1,2*

Program in Molecular Biology,1 Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80262,2 Department of Molecular Genetics, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel3

Received 12 November 2001/ Returned for modification 31 December 2001/ Accepted 25 April 2002

The progesterone receptor (PR) contains two transcription activation function (AF) domains, constitutive AF-1 in the N terminus and AF-2 in the C terminus. AF-2 activity is mediated by a hormone-dependent interaction with a family of steroid receptor coactivators (SRCs). SRC-1 can also stimulate AF-1 activity through a secondary domain that interacts simultaneously with the primary AF-2 interaction site. Other protein interactions and mechanisms that mediate AF-1 activity are not well defined. By interaction cloning, we identified an AP-1 family member, Jun dimerization protein 2 (JDP-2), as a novel PR-interacting protein. JDP-2 was first defined as a c-Jun interacting protein that functions as an AP-1 repressor. PR and JDP-2 interact directly in vitro through the DNA binding domain (DBD) of PR and the basic leucine zipper (bZIP) region of JDP-2. The two proteins also physically associate in mammalian cells, as detected by coimmunoprecipitation, and are recruited in vivo to a progesterone-inducible target gene promoter, as detected by a chromatin immunoprecipitation (ChIP) assay. In cell transfection assays, JDP-2 substantially increased hormone-dependent PR-mediated transactivation and worked primarily by stimulating AF-1 activity. JDP-2 is a substantially stronger coactivator of AF-1 than SRC-1 and stimulates AF-1 independent of SRC-1 pathways. The PR DBD is necessary but not sufficient for JDP-2 stimulation of PR activity; the DBD and AF-1 are required together. JDP-2 lacks an intrinsic activation domain and makes direct protein interactions with other coactivators, including CBP and p300 CBP-associated factor (pCAF), but not with SRCs. These results indicate that JDP-2 stimulates AF-1 activity by the novel mechanism of docking to the DBD and recruiting or stabilizing N-terminal PR interactions with other general coactivators. JDP-2 has preferential activity on PR among the nuclear receptors tested and is expressed in progesterone target cells and tissues, suggesting that it has a physiological role in PR function.

* Corresponding author. Mailing address: Department of Pathology, University of Colorado Health Sciences Center, Denver, CO 80262. Phone: (303) 315-5416. Fax: (303) 315-6721. E-mail: Dean.Edwards{at}uchsc.edu.

Molecular and Cellular Biology, August 2002, p. 5451-5466, Vol. 22, No. 15
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.15.5451-5466.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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