title: Molecular evidence of functional progesterone withdrawal in human myometrium.
abstract: Progesterone suppresses uterine contractility acting through its receptors (PRA/B). The mechanism by which human labour is initiated in the presence of elevated circulating progesterone has remained an enigma since Csapo first theorized of a functional withdrawal of progesterone in 1965. Here we report that in vitro progesterone-liganded nuclear PRB forms a complex including JUN/JUN homodimers and P54(nrb)/Sin3A/HDAC to repress transcription of the key labour gene, Cx43. In contrast, unliganded PRA paradoxically activates Cx43 transcription by interacting with FRA2/JUND heterodimers. Furthermore, we find that while nuclear progesterone receptor (PR) is liganded during human pregnancy, it becomes unliganded during both term and preterm labour as a result of increased expression of the progesterone-metabolizing enzyme 20α HSD and reduced nuclear progesterone levels. Our data provide a mechanism by which human labour can occur in the presence of elevated circulating progesterone and suggests non-metabolizable progestogen might represent an alternative new therapeutic approach to preterm birth prevention.
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5T 3H7.
authors.forename: Lubna
authors.initials: L
authors.lastname: Nadeem
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5T 3H7.|Department of Obstetrics &Gynecology, University of Toronto, Toronto, Ontario, Canada M5G 1E2.
authors.forename: Oksana
authors.initials: O
authors.lastname: Shynlova
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5T 3H7.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Matysiak-Zablocki
authors.affiliation: Department of Reproductive Biology, Case Western Reserve University, Cleveland, Ohio 44106-5034, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Mesiano
authors.affiliation: Department of Obstetrics &Gynecology, University of Toronto, Toronto, Ontario, Canada M5G 1E2.|Department of Urologic Sciences, Vancouver Prostate Centre, University of BC, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: Xuesen
authors.initials: X
authors.lastname: Dong
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5T 3H7.|Department of Obstetrics &Gynecology, University of Toronto, Toronto, Ontario, Canada M5G 1E2.|Department of Physiology University of Toronto, Toronto, Ontario, Canada M5S 1A1.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lye
mesh_terms: D000818:Animals; D018031:Connexin 43 / Q000378:metabolism*; D019281:Dimerization; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D007743:Labor, Obstetric / Q000378:metabolism*; D051379:Mice; D009215:Myometrium / Q000378:metabolism*; D007752:Obstetric Labor, Premature / Q000378:metabolism; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D018031:Connexin 43; D016761:Oncogene Proteins v-fos; D016755:Proto-Oncogene Proteins c-jun; D011980:Receptors, Progesterone; D018808:Transcription Factor AP-1; C101118:progesterone receptor A; C097314:progesterone receptor B; D011374:Progesterone; D006913:Hydroxysteroid Dehydrogenases