title: Progesterone-Dependent Induction of Phospholipase C-Related Catalytically Inactive Protein 1 (PRIP-1) in Decidualizing Human Endometrial Stromal Cells.
abstract: Decidualization denotes the transformation of endometrial stromal cells into specialized decidual cells. In pregnancy, decidual cells form a protective matrix around the implanting embryo, enabling coordinated trophoblast invasion and formation of a functional placenta. Continuous progesterone (P4) signaling renders decidual cells resistant to various environmental stressors, whereas withdrawal inevitably triggers tissue breakdown and menstruation or miscarriage. Here, we show that PLCL1, coding phospholipase C (PLC)-related catalytically inactive protein 1 (PRIP-1), is highly induced in response to P4 signaling in decidualizing human endometrial stromal cells (HESCs). Knockdown experiments in undifferentiated HESCs revealed that PRIP-1 maintains basal phosphoinositide 3-kinase/Protein kinase B activity, which in turn prevents illicit nuclear translocation of the transcription factor forkhead box protein O1 and induction of the apoptotic activator BIM. By contrast, loss of this scaffold protein did not compromise survival of decidual cells. PRIP-1 knockdown did also not interfere with the responsiveness of HESCs to deciduogenic cues, although the overall expression of differentiation markers, such as PRL, IGFBP1, and WNT4, was blunted. Finally, we show that PRIP-1 in decidual cells uncouples PLC activation from intracellular Ca(2+) release by attenuating inositol 1,4,5-trisphosphate signaling. In summary, PRIP-1 is a multifaceted P4-inducible scaffold protein that gates the activity of major signal transduction pathways in the endometrium. It prevents apoptosis of proliferating stromal cells and contributes to the relative autonomy of decidual cells by silencing PLC signaling downstream of Gq protein-coupled receptors.
authors.affiliation: Division of Biomedical Sciences (J.M., P.J.B., E.S.L., L.L., A.S., S.Q., A.M.B., J.J.B.), Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom; and University Hospitals Coventry and Warwickshire National Health Service Trust (S.Q., J.J.B.), Coventry, CV2 2DX United Kingdom; and Tommy's National Miscarriage Research Centre (E.S.L., S.Q., J.J.B.), University Hospital Coventry and Warwickshire, Coventry, CV2 2DX United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Muter
authors.affiliation: Division of Biomedical Sciences (J.M., P.J.B., E.S.L., L.L., A.S., S.Q., A.M.B., J.J.B.), Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom; and University Hospitals Coventry and Warwickshire National Health Service Trust (S.Q., J.J.B.), Coventry, CV2 2DX United Kingdom; and Tommy's National Miscarriage Research Centre (E.S.L., S.Q., J.J.B.), University Hospital Coventry and Warwickshire, Coventry, CV2 2DX United Kingdom.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Brighton
authors.affiliation: Division of Biomedical Sciences (J.M., P.J.B., E.S.L., L.L., A.S., S.Q., A.M.B., J.J.B.), Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom; and University Hospitals Coventry and Warwickshire National Health Service Trust (S.Q., J.J.B.), Coventry, CV2 2DX United Kingdom; and Tommy's National Miscarriage Research Centre (E.S.L., S.Q., J.J.B.), University Hospital Coventry and Warwickshire, Coventry, CV2 2DX United Kingdom.
authors.forename: Emma S
authors.initials: ES
authors.lastname: Lucas
authors.affiliation: Division of Biomedical Sciences (J.M., P.J.B., E.S.L., L.L., A.S., S.Q., A.M.B., J.J.B.), Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom; and University Hospitals Coventry and Warwickshire National Health Service Trust (S.Q., J.J.B.), Coventry, CV2 2DX United Kingdom; and Tommy's National Miscarriage Research Centre (E.S.L., S.Q., J.J.B.), University Hospital Coventry and Warwickshire, Coventry, CV2 2DX United Kingdom.
authors.forename: Lauren
authors.initials: L
authors.lastname: Lacey
authors.affiliation: Division of Biomedical Sciences (J.M., P.J.B., E.S.L., L.L., A.S., S.Q., A.M.B., J.J.B.), Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom; and University Hospitals Coventry and Warwickshire National Health Service Trust (S.Q., J.J.B.), Coventry, CV2 2DX United Kingdom; and Tommy's National Miscarriage Research Centre (E.S.L., S.Q., J.J.B.), University Hospital Coventry and Warwickshire, Coventry, CV2 2DX United Kingdom.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Shmygol
authors.affiliation: Division of Biomedical Sciences (J.M., P.J.B., E.S.L., L.L., A.S., S.Q., A.M.B., J.J.B.), Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom; and University Hospitals Coventry and Warwickshire National Health Service Trust (S.Q., J.J.B.), Coventry, CV2 2DX United Kingdom; and Tommy's National Miscarriage Research Centre (E.S.L., S.Q., J.J.B.), University Hospital Coventry and Warwickshire, Coventry, CV2 2DX United Kingdom.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Quenby
authors.affiliation: Division of Biomedical Sciences (J.M., P.J.B., E.S.L., L.L., A.S., S.Q., A.M.B., J.J.B.), Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom; and University Hospitals Coventry and Warwickshire National Health Service Trust (S.Q., J.J.B.), Coventry, CV2 2DX United Kingdom; and Tommy's National Miscarriage Research Centre (E.S.L., S.Q., J.J.B.), University Hospital Coventry and Warwickshire, Coventry, CV2 2DX United Kingdom.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Blanks
authors.affiliation: Division of Biomedical Sciences (J.M., P.J.B., E.S.L., L.L., A.S., S.Q., A.M.B., J.J.B.), Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom; and University Hospitals Coventry and Warwickshire National Health Service Trust (S.Q., J.J.B.), Coventry, CV2 2DX United Kingdom; and Tommy's National Miscarriage Research Centre (E.S.L., S.Q., J.J.B.), University Hospital Coventry and Warwickshire, Coventry, CV2 2DX United Kingdom.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Brosens
mesh_terms: D000328:Adult; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004717:Endometrium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D056918:Nuclear Receptor Coactivators / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: C486559:NCOA6 protein, human; D056918:Nuclear Receptor Coactivators; D017258:Medroxyprogesterone Acetate