Interplay between estrogens, progestins, retinoic acid and AP-1 on a single regulatory site in the progesterone receptor gene.
Transcriptional regulation of the progesterone receptor gene involves induction by estrogens and down-regulation by progestins, retinoic acid, and AP-1 proteins. We have previously identified an intragenic (+698/+723) estrogen-responsive element present in the progesterone receptor gene, which binds the estradiol receptor and mediates estrogen and 4-OH tamoxifen induction. Progesterone receptor gene expression was equally stimulated by estradiol and 4-OH tamoxifen in the presence of a NH2 terminally deleted estrogen receptor mutant lacking activation function 1, suggesting that activation function 2 was the predominant activation domain. This was confirmed by the lack of activity of an estrogen receptor mutant deleted of activation function 2. Repression by progestins, retinoic acid, and AP-1 was mediated by the same estrogen responsive element although retinoic and progesterone receptors as well as AP-1 proteins did not bind to this element. Repression by these proteins appears to involve different transactivating regions of the estrogen receptor. Repression by retinoic receptors involved only activation function 2 whereas repression by progesterone receptor and AP-1 necessitated both functional domains. Since these proteins act without directly contacting the DNA, it seems likely that repression may be achieved by protein-protein interactions among different domains of the estrogen receptor and/or the transcriptional machinery.
INSERM Unit 135, Hopital de Bicêtre, Le Kremlin-Bicêtre, France.
J F
JF
Savouret
M
M
Rauch
G
G
Redeuilh
S
S
Sar
A
A
Chauchereau
K
K
Woodruff
M G
MG
Parker
E
E
Milgrom
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004967:Estrogens / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D011372:Progestins / Q000378:metabolism*; D011817:Rabbits; D011980:Receptors, Progesterone / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism*
D004967:Estrogens; D011372:Progestins; D011980:Receptors, Progesterone; D018808:Transcription Factor AP-1; D014212:Tretinoin