Progesterone receptor membrane component 1 and its role in ovarian follicle growth

Abstract

Progesterone (P4) is synthesized in the ovary and acts directly on granulosa cells of developing ovarian follicles to suppress their rate of mitosis and apoptosis. Granulosa cells do not express nuclear progesterone receptor (PGR) but rather progesterone receptor membrane component-1 (PGRMC1). PGRMC1 binds P4 and mediates P4's actions, as evidenced by PGRMC1 siRNA studies. PGRMC1 acts by binding plasminogen activator inhibitor 1 RNA-binding protein and regulating gene expression. Specifically, PGRMC1 suppresses some genes that promote cell death (i.e., Bad, Caspase-3, Caspase-4). P4 regulates gene expression in part by inhibiting PGRMC1 binding to Tcf/Lef transcription sites, thereby reducing Tcf/Lef transcriptional activity. Since Tcf/Lef transcription sites are located within the promoters of genes that initiate mitosis and/or apoptosis (i.e., c-jun and c-myc), P4-PGRMC1 mediated suppression of these Tcf/Lef regulated genes could account for P4's actions. PGRMC1 expression is also altered in women with polycystic ovarian syndrome, premature ovarian failure and infertility. Collectively, these observations support a role for PGRMC1 in regulating human ovarian follicle development.

Progesterone Receptor Membrane Component 1 Is a Functional Part of the Glucagon-like Peptide-1 (GLP-1) Receptor Complex in Pancreatic β Cells

“…It is known that progesterone (P4) binds to PGRMC1 with high affinity in mammalian cells and that PGRMC1 mediates P4 function (32)(33)(34). We observed that the overexpression of PGRMC1 increased GIIS significantly with multiple GLP-1 doses in INS1 832/3 cells (Fig.…”

“…It also has the ability to bind other molecules, including testosterone, glucocorticoids, heme, and cholesterol metabolites (32,33). Recently it was discovered that PGRMC1 binds -2 receptor ligands, indicating that the PGRMC1 complex is a putative -2 receptor-binding site (40).…”

Progesterone receptor membrane component 1 promotes survival of human breast cancer cells and the growth of xenograft tumors

“…24 Similar findings have been established in human granulosa/ luteal cells and spontaneously immortalized granulosa cells (SIGCs). 40 Depletion of PGRMC1 using siRNA eliminates the anti-mitotic actions of P4, suggesting that P4 activation of PGRMC1 is necessary for blocking progression through the cell cycle in granulosa cells. 41 More recently, PGRMC1 was shown to interact with PGRMC2 to suppress entry of SIGCs into the cell cycle.…”

PGRMC1 participates in late events of bovine granulosa cells mitosis and oocyte meiosis

“…[6][7][8] Primary evidence that PGRMC1 has a fundamental role in ovarian somatic cells comes from in vivo studies in mice, in which conditional knockout of PGRMC1 in granulosa cells impairs antral follicle development. 2,9 Accordingly, in vitro studies using different ovarian cell lines have shown that depleting PGRMC1 expression suppresses cell proliferation. [10][11][12] However the mechanism of action by which PGRMC1 controls ovarian cell proliferation is poorly understood.…”

“…1,2 Within the ovary, PGRMC1 is expressed and exerts a function in both somatic and germ cells. [3][4][5] Its clinical relevance is indicated by studies showing that altered PGRMC1 expression correlates with defective follicular development and infertility in women.…”