Human Parturition Involves Phosphorylation of Progesterone Receptor-A at Serine-345 in Myometrial Cells
| Autor: | Yelenna Skomorovska-Prokvolit, Kelly Kuo, Daniel Michniuk, Peyvand Amini, Huiqing Tan, Lijuan Yi, Sam Mesiano, Junye Wang, Charles J. Malemud, Gregory A. Peters |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Progesterone receptor A Biology In Vitro Techniques Proinflammatory cytokine Cell Line Serine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology Internal medicine Progesterone receptor medicine Humans Phosphorylation Progesterone Original Research 030219 obstetrics & reproductive medicine Myometrium Parturition Immunohistochemistry female genital diseases and pregnancy complications 030104 developmental biology chemistry Cell culture Phosphoserine Mutagenesis Site-Directed Female Receptors Progesterone Multiplex Polymerase Chain Reaction hormones hormone substitutes and hormone antagonists |
| Popis: | The hypothesis that phosphorylation of progesterone receptor (PR) isoforms, PR-A and PR-B, in myometrial cells affects progesterone action in the context of human parturition was tested. Immunodetection of phosphoserine (pSer) PR forms in term myometrium revealed that the onset of labor is associated with increased phosphorylation of PR-A at serine-345 (pSer345-PRA) and that pSer345-PRA localized to the nucleus of myometrial cells. In explant cultures of term myometrium generation of pSer345-PRA was induced by interleukin-1β and dependent on progesterone, suggesting that pSer345-PRA generation is induced by a proinflammatory stimulus. In the hTERT-HMA/B human myometrial cell line, abundance of pSer345-PRA was induced by progesterone in a dose- (EC50 ∼1 nM) and time-dependent manner. Prevention of pSer345 (by site-directed mutagenesis) abolished the capacity for PR-A to inhibit anti-inflammatory actions of progesterone mediated by PR-B but had no effect on the transrepressive activity of PR-A at a canonical progesterone response element. Taken together, the data show that human parturition involves the phosphorylation of PR-A at serine-345 in myometrial cells and that this process is ligand dependent and induced by a proinflammatory stimulus. We also found that in myometrial cells, pSer345 activates the capacity for PR-A to inhibit antiinflammatory actions of progesterone mediated by PR-B. Phosphorylation of PR-A at serine-345 may be an important functional link between tissue-level inflammation and PR-A-mediated functional progesterone withdrawal to trigger parturition. |
| Databáze: | OpenAIRE |
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