Jun dimerization protein 2 functions as a progesterone receptor N-terminal domain coactivator.
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.
Wardell
Suzanne E
SE
Program in Molecular Biology, Department of Pathology, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Boonyaratanakornkit
Viroj
V
Adelman
James S
JS
Aronheim
Ami
A
Edwards
Dean P
DP
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000235:genetics; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D016350:Leucine Zippers / Q000502:physiology; D046911:Macromolecular Substances; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008969:Molecular Sequence Data; D056920:Nuclear Receptor Coactivator 1; D011233:Precipitin Tests; D045167:Progesterone Congeners / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D011980:Receptors, Progesterone / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014162:Transfection
C106159:Batf3 protein, rat; D002843:Chromatin; C484558:DNAJC12 protein, human; D006727:Hormone Antagonists; C491387:JDP2 protein, human; C106160:Jdp2 protein, rat; C491386:Jundp2 protein, mouse; D046911:Macromolecular Substances; D045167:Progesterone Congeners; D011980:Receptors, Progesterone; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D005982:Glutathione Transferase