Interference between progesterone and dioxin signal transduction pathways. Different mechanisms are involved in repression by the progesterone receptor A and B isoforms.
Interactions between transcription factors are an important means of regulating gene transcription, leading to modifications in the pattern of gene expression and cell fate. In this study, we report that the progesterone receptor (PR) can strongly interfere with transactivation mediated by the arylhydrocarbon receptor (AhR) in T47D breast cancer cells. This interference was not only demonstrated by induction of a transfected dioxin-responsive reporter plasmid but also on the AhR-mediated up-regulation of the endogenous cytochrome P450-1A1 activity. The interference was not mutual, as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent activator of the AhR, did not inhibit progestin-induced promoter activity. When the isoforms of the human PR, hPR-A and hPR-B, were expressed separately in HepG-2 hepatocarcinoma cells, both negatively interfered with the AhR signaling, indicating that the effect is not restricted to T47D cells. In addition, results obtained from studies with both antiprogestins and mutant receptors indicate differences in the underlying molecular mechanisms of repression for both PR isoforms. The suppression by hPR-A does not require additional gene expression or a full transcriptional competent conformation of the receptor. For the repressive effects of hPR-B, however, additional gene expression seems to be involved, as only the agonist-bound, wild-type hPR-B could clearly repress the TCDD-induced response. In conclusion, these studies highlight different mechanisms of repression for the progesterone receptor isoforms on the AhR-mediated trans-activation and underscore the importance of interactions between transcription factors of different families in the regulation of gene transcription.
Kuil
C W
CW
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands. kuil@niob.knaw.nl
Brouwer
A
A
van der Saag
P T
PT
van der Burg
B
B
D001943:Breast Neoplasms; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006067:Gonanes / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011282:Pregnenediones / Q000494:pharmacology; D045167:Progesterone Congeners / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D006067:Gonanes; D006727:Hormone Antagonists; D000072317:Polychlorinated Dibenzodioxins; D011282:Pregnenediones; D045167:Progesterone Congeners; D018336:Receptors, Aryl Hydrocarbon; D011980:Receptors, Progesterone; D011994:Recombinant Proteins; C101118:progesterone receptor A; C097314:progesterone receptor B; C020175:16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione; D015735:Mifepristone; D019363:Cytochrome P-450 CYP1A1; C053238:onapristone