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The leucine zippers of c-fos and c-jun for progesterone receptor dimerization: A-dominance in the A/B heterodimer
| Content Provider | Semantic Scholar |
|---|---|
| Author | Mohamed, Mohamed K. Tung, Lin Takimoto, Glenn S. Horwitz, Kathryn B. |
| Copyright Year | 1994 |
| Abstract | Human progesterone receptors (hPR) exist as two isoforms: 120 kDa B-receptors (hPRB) and N-terminally truncated 94 kDa A-receptors (hPRA). When transfected separately, each isoform exhibits different transcriptional properties that are ligand- and promoter-specific. In human target tissues, both receptor isoforms are present, so that a mixture of three dimeric species, A/A, A/B, and B/B, bind to DNA at progesterone response elements (PRE), and regulate transcription. To study the transcriptional phenotype of pure A/B heterodimers uncontaminated by A/A or B/B homodimers, we exploited the property of the leucine zipper (zip) domains of fos and jun, to form pure heterodimers. Chimeric constructs were made linking the zip of either c-fos or c-jun to the C-terminus of hPRB or hPRA (hPR-zip) to produce A-fos, B-fos, A-jun or B-jun. To determine whether the A- or B-isoform is functionally dominant in the A/B heterodimer, cells expressing hPR-zip chimeras were treated with the progestin antagonist RU486, which produces opposite transcriptional effects with the two isoforms. Gel mobility shift and immune co-precipitation assays show that in the presence of RU486 only pure heterodimers form between A-fos/B-jun or A-jun/B-fos, and bind DNA at PREs. Thus, in these pairs, interactions between the extrinsic fos/jun zipper domains override interactions between the intrinsic hPR dimerization domains. We find that under these conditions, antagonist-occupied B-zip homodimers stimulate transcription, while antagonist-occupied A-zip homodimers are inhibitory, and that pure A/B zip heterodimers have the inhibitory transcriptional phenotype of the A-zip homodimers. We conclude that, in pure heterodimers, A-receptors are dominant negative inhibitors of B-receptors. Additionally, the pure PR-zip heterodimers, unlike wild-type receptors, bind a PRE in the absence of hormone but do not activate transcription. Thus, PR dimerization and PRE binding are necessary but, without hormone, not sufficient to activate transcription. |
| Starting Page | 241 |
| Ending Page | 250 |
| Page Count | 10 |
| File Format | PDF HTM / HTML |
| DOI | 10.1016/0960-0760(94)90036-1 |
| PubMed reference number | 7826885 |
| Journal | Medline |
| Volume Number | 51 |
| Alternate Webpage(s) | https://api.elsevier.com/content/article/pii/0960076094900361 |
| Alternate Webpage(s) | https://www.sciencedirect.com/science/article/pii/0960076094900361?dgcid=api_sd_search-api-endpoint |
| Alternate Webpage(s) | https://doi.org/10.1016/0960-0760%2894%2990036-1 |
| Journal | The Journal of Steroid Biochemistry and Molecular Biology |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
