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Progesterone Activates a Progesterone Receptor Membrane Component 1-Dependent Mechanism That Promotes Human Granulosa/Luteal Cell Survival But Not Progesterone Secretion

Departments of Cell Biology (J.J.P., X.L., A.G.) and Obstetrics and Gynecology (J.J.P., E.J.-M.), University of Connecticut Health Center, Farmington, Connecticut 06030

Address all correspondence and requests for reprints to: John J. Peluso, Ph.D., Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030. E-mail: peluso{at}nso2.uchc.edu.

Context: Progesterone (P4) promotes its own secretion and the survival of human granulosa/luteal (GL) cells.

Objective: The objective of these studies was to determine whether progesterone receptor membrane component-1 (PGRMC1) mediates P4’s actions.

Design: In vitro studies were conducted on GL cells from women undergoing in vitro fertilization and GL5 cells, which are derived from GL cells.

Setting and Patients: GL cells were obtained from women undergoing fertility treatment at a university-based clinic and used for in vitro studies.

Main Outcome Measures: PCR, Western blot, and immunocytochemistry were used to detect various progestin binding proteins. ³H-P4 binding kinetics were assessed on partially purified PGRMC1. Apoptosis was determined after culture by either TUNEL or DAPI staining. P4 was measured by an ELISA assay. PGRMC1 was depleted using small interfering RNA.

Results: GL and GL5 cells expressed several P4 binding proteins including the nuclear progesterone receptor (PGR), progestin/adipoQ receptors (PAQR 7, 8, and 5) and PGRMC1. Ligand binding studies revealed that both P4 and the progestin, R5020, bound PGRMC1 with an EC₅₀ of approximately 10 nM. Interestingly, P4 inhibited apoptosis at concentrations in the 10 nM range, whereas R5020 stimulated P4 secretion at concentrations of at lease 16 µM. Depleting PGRMC1 attenuated P4’s antiapoptotic action but failed to influence R5020-induced P4 secretion.

Conclusions: These studies conclusively demonstrate that in human GL cells PGRMC1 functions as a receptor through which P4 activates a signal cascade that prevents apoptosis. In contrast, PGRMC1 does not mediate P4’s ability to acutely promote its own secretion.