An N-terminally truncated third progesterone receptor protein, PR(C), forms heterodimers with PR(B) but interferes in PR(B)-DNA binding.
Multiple progesterone receptor (PR) isoforms may explain in part the complex and diverse biological actions of progestins. Recent studies demonstrate that the human 116 kDa B-receptor (PR[B]) and the 94 kDa A-receptor (PR[A]) can have very different transcriptional functions that are cell- and promoter-specific. Additionally, we have shown the existence of a smaller N-terminally truncated 60 kDa progestin-specific binding protein, called the C-receptor (PR[C]), that has unique transcriptional potentiating properties. In the presence of the other two PR isoforms, PR(C) enhances the transcriptional activities of the larger PR proteins. In order to determine the mechanism of action for the transcriptional promoting abilities of PR(C), the structural and functional properties of PR(C) were analysed and compared to those of PR(A) and PR(B). PR(C) consistently displayed a dissociation constant (Kd) approximately 5 times higher than that for PR(B) and PR(A), suggesting that the N-terminal truncation of PR(C) results in a conformation different from the two larger PR isoforms, that affects the hormone-binding region and its interaction with hormone. Despite this change, PR(C) is still capable of forming heterodimers with the larger PR(B) in solution, as determined by co-immunoprecipitation studies, but PR(C) interferes in tight PR(B) binding to DNA in gel-shift assays. Surprisingly, progestin and antiprogestin autoregulation of PR(C) protein levels parallel those for PR(B) and PR(A).
Wei
L L
LL
The Vincent T. Lombardi Cancer Center, Georgetown University, Washington, DC 20007, USA.
Norris
B M
BM
Baker
C J
CJ
D001667:Binding, Competitive / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D011372:Progestins / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D011980:Receptors, Progesterone / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D011372:Progestins; D011980:Receptors, Progesterone