ANTAGONIST-OCCUPIED HUMAN PROGESTERONE B-RECEPTORS ACTIVATE TRANSCRIPTION WITHOUT BINDING TO PROGESTERONE RESPONSE ELEMENTS AND ARE DOMINANTLY INHIBITED BY A-RECEPTORS
L. Tung et al., ANTAGONIST-OCCUPIED HUMAN PROGESTERONE B-RECEPTORS ACTIVATE TRANSCRIPTION WITHOUT BINDING TO PROGESTERONE RESPONSE ELEMENTS AND ARE DOMINANTLY INHIBITED BY A-RECEPTORS, Molecular endocrinology, 7(10), 1993, pp. 1256-1265
When antagonist-occupied steroid receptors have agonist-like effects,
the clinical consequences are grave. We present evidence that human pr
ogesterone B-receptors (hPR(B)) when occupied by progesterone antagoni
sts, inappropriately activate transcription by an unusual mechanism th
at does not require the canonical progesterone response element (PRE).
In HeLa cells cotransfected with a PRE-tk-chloramphenicol acetyltrans
ferase reporter and a hPR(B) expression vector, strong transcription i
s seen not only when receptors are activated by the agonist R5020, but
also in the presence of the three antiprogestins, RU486, ZK112993, an
d ZK98299. Human PR(B) occupied by ZK98299 do not bind to a PRE, sugge
sting that the transcriptional stimulation is independent of DNA bindi
ng. Indeed, a tk-chloramphenicol acetyltransferase promoter-reporter l
acking the PRE loses transcriptional activation by the agonist, but re
tains transactivation by the three antagonists. The PRE-independent an
tagonist-induced transcription requires that hPR(B) have an intact DNA
-binding domain, but hPR target gene specificity is not required, beca
use a hPR(B) mutant that binds an estrogen response element still acti
vates transcription. It appears that antagonist-occupied hPR activate
transcription without binding to a PRE, perhaps by interacting with te
thering proteins instead. Even a gene that is not a normal progesteron
e target could be aberrantly activated. Human cells contain equimolar
amounts of hPR(B) and the N-terminally truncated natural isotype, hPR(
A). Unlike hPR(B), hPR(A) are not transcriptionally activated by proge
sterone antagonists. We, therefore, tested the effects of antagonists
when the two receptor isotypes are coexpressed and found that A-recept
ors can annul the inappropriate transcription by B-receptors. Thus, wh
en both receptor forms are present, the hPR(A) phenotype is dominant.
Moreover, pure hPR(B)/hPR(A) heterodimers, produced by fos/jun leucine
zipper domain-hPR chimeras, also have the inactive transcriptional ph
enotype of hPR(A). Our studies suggest not only that the two hPR isoty
pes are functionally quite different, but also that some of the agonis
t-like transcriptional effects of antagonist-occupied B-receptors proc
eed through novel mechanisms.