Selective and opposing actions of progesterone receptor isoforms in human endometrial stromal cells.
Transcriptional regulation by progesterone is mediated primarily through the two progesterone receptor (PR) isoforms, PR-A and PR-B. Primary human endometrial stromal cell cultures, in which endogenous PR expression was lost, were infected with adenovirus expressing PR-A, PR-B, or both. Global gene expression analysis was conducted on vehicle and 30 nM progesterone (P4) treated cells following 12 h treatment. Interestingly, many genes regulated by PR-B alone or upon PR-A and PR-B co-expression, did not overlap with each other or with the PR-A expression group. Although many genes known to be progestin regulated in the uterus in vivo were also regulated in this study, markedly little overlap with published P4 regulated genes from human breast cancer cells was observed. Progesterone dose response curves were generated for several genes demonstrating gene selective potency and efficacy for each PR isoform. Furthermore, the PR isoforms opposed each other in regulation of tissue factor, with PR-B increasing and PR-A decreasing both mRNA and protein levels. Our data provide a view of global gene expression by PR isoforms in human endometrial cells and a comparison with other cell types. The specific genes and regulation patterns found provide groundwork to revealing the mechanism of PR isoform selectivity, and perhaps ultimately to the tissue selective properties these receptors appear to exhibit.
Yudt
M R
MR
Women's Health Research Institute, Wyeth Research, Collegeville, PA 19426, USA. yudtm@wyeth.com
Berrodin
T J
TJ
Jelinsky
S A
SA
Hanna
L A
LA
Brown
E L
EL
Chippari
S
S
Bhat
R A
RA
Winneker
R C
RC
Zhang
Z
Z
D002478:Cells, Cultured; D004717:Endometrium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D011374:Progesterone / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics* / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism
D020033:Protein Isoforms; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D011374:Progesterone