Human Parturition Involves Phosphorylation of Progesterone Receptor-A at Serine-345 in Myometrial Cells

The mechanism that initiates human parturition has been proposed to be functional progesterone withdrawal whereby the 116-kDa B isoform of the progesterone receptor (PR-B) switches in favor of the 94-kDa A isoform (PR-A) in reproductive tissues. Recently other PR isoforms, PR-S, PR-C, and PR-M generated from the same gene have been identified and partially characterized. Using immunohistochemical, Western blotting, and RT-PCR techniques, evidence is provided that the major PR isoform present in human term fetal membranes (amnion and chorion) and syncytiotrophoblast of the placenta is neither of the classical nuclear PR-B or PR-A isoforms but is the N terminally truncated 60-kDa PR-C isoform. Evidence is also provided that the PR-C isoform resides in the cytoplasm of the expressing cell types. Data are also presented to show that PR-B, PR-A, and PR-S isoforms are essentially absent from the amnion and chorion, whereas PR isoforms A, B, C, and S are all present in the decidua, with PR-A being the major isoform. The syncytiotrophoblast of the placenta contains the cytoplasmic PR-C isoform but not PR-A, PR-B, or PR-S. The major PR isoform in the amnion, chorion, and placenta is PR-C, suggesting that the cytoplasmic PR-C isoform has a specific role in extraembryonic tissues and may be involved in the regulation of human parturition.

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Prostaglandins Differentially Modulate Progesterone Receptor-A and -B Expression in Human Myometrial Cells: Evidence for Prostaglandin-Induced Functional Progesterone Withdrawl

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-031037 ◽

2004 ◽

Vol 89 (2) ◽

pp. 1010-1013 ◽

Cited By ~ 92

Author(s):

Gemma Madsen ◽

Tamas Zakar ◽

Chun Ying Ku ◽

Barbara M. Sanborn ◽

Roger Smith ◽

...

Keyword(s):

Progesterone Receptor ◽

Myometrial Cells

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Progesterone Withdrawal and Estrogen Activation in Human Parturition Are Coordinated by Progesterone Receptor A Expression in the Myometrium

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.87.6.8609 ◽

2002 ◽

Vol 87 (6) ◽

pp. 2924-2930 ◽

Cited By ~ 211

Author(s):

Sam Mesiano ◽

Eng-Cheng Chan ◽

John T. Fitter ◽

Kenneth Kwek ◽

George Yeo ◽

...

Keyword(s):

Progesterone Receptor ◽

Human Parturition

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Selective Progesterone Receptor Modulator Asoprisnil (J867) Inhibits Proliferation and Induces Apoptosis in Cultured Uterine Leiomyoma Cells But Not in Cultured Normal Myometrial Cells

Fertility and Sterility ◽

10.1016/j.fertnstert.2005.07.368 ◽

2005 ◽

Vol 84 ◽

pp. S152 ◽

Cited By ~ 1

Author(s):

W. Chen

Keyword(s):

Progesterone Receptor ◽

Uterine Leiomyoma ◽

Myometrial Cells ◽

Receptor Modulator

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Progesterone Receptor Plays a Major Antiinflammatory Role in Human Myometrial Cells by Antagonism of Nuclear Factor-κB Activation of Cyclooxygenase 2 Expression

Molecular Endocrinology ◽

10.1210/me.2006-0112 ◽

2006 ◽

Vol 20 (11) ◽

pp. 2724-2733 ◽

Cited By ~ 176

Author(s):

Daniel B. Hardy ◽

Bethany A. Janowski ◽

David R. Corey ◽

Carole R. Mendelson

Keyword(s):

Progesterone Receptor ◽

Target Genes ◽

Nuclear Factor Κb ◽

Inhibitory Effect ◽

Cyclooxygenase 2 ◽

Nuclear Factor ◽

Uterine Contractility ◽

T47d Cells ◽

Myometrial Cells ◽

Cox 2

Abstract Spontaneous labor in women and in other mammals is likely mediated by a concerted series of biochemical events that negatively impact the ability of the progesterone receptor (PR) to regulate target genes that maintain myometrial quiescence. In the present study, we tested the hypothesis that progesterone/PR inhibits uterine contractility by blocking nuclear factor κB (NF-κB) activation and induction of cyclooxygenase-2 (COX-2), a contractile gene that is up-regulated in labor. To uncover mechanisms for regulation of uterine COX-2, immortalized human fundal myometrial cells were treated with IL-1β ± progesterone. IL-1β alone caused a marked up-regulation of COX-2 mRNA, whereas treatment with progesterone suppressed this induction. This was also observed in human breast cancer (T47D) cells. In both cell lines, this inhibitory effect of progesterone was blocked by RU486. Using chromatin immunoprecipitation, we observed that IL-1β stimulated recruitment of NF-κB p65 to both proximal and distal NF-κB elements of the COX-2 promoter; these effects were diminished by coincubation with progesterone. The ability of progesterone to inhibit COX-2 expression in myometrial cells was associated with rapid induction of mRNA and protein levels of inhibitor of κBα, a protein that blocks NF-κB transactivation. Furthermore, small interfering RNA-mediated ablation of both PR-A and PR-B isoforms in T47D cells greatly enhanced NF-κB activation and COX-2 expression. These effects were observed in the absence of exogenous progesterone, suggesting a ligand-independent action of PR. Based on these findings, we propose that PR may inhibit NF-κB activation of COX-2 gene expression and uterine contractility via ligand-dependent and ligand-independent mechanisms.

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