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.

Keywords: apoptosis; mitosis; ovary; progesterone; progesterone receptor membrane component 1.

Figure 1

Progesterone (P4)-PGRMC1 interactions. (A) Shows a ligand-binding analysis of ³H-P4 to partially purified PGRMC1-GFP fusion protein. Specific ³H-P4-binding decreased with the addition of non-radioactive P4. Hill plot analysis (inset) yielded a straight line with a slope of 1.08, indicting that ³H-P4 specifically bound to PGRMC1-GFP in a competitive and reversible manner (Data from Figure 6 from Peluso et al., 2008). The effect of PGRMC1 siRNA on SIGC proliferation (B) apoptosis (C) and the percentage of cells in the metaphase stage of the cell cycle (D). ^*Indicates a value that is significantly different (p < 0.05) from scramble control (∅).

Figure 2

In (A) the co-localization of β-tubulin (green) and PGRMC1 (red) in relationship to metaphase chromosomes (blue) is shown in SKOV3 cell. Also shown is interaction between PGRMC1 and β-tubulin as revealed by in situ Proximity Ligation Assay (PLA). The presence of red fluorescent dots in the PLA assay indicates that two proteins are in close proximity (i.e., interacting). DNA is counterstained with DAPI (blue). Negative controls were conducted and did not show any staining. (Images are from Figures 5 to 7 from Lodde and Peluso, 2011). (B) Shows the number of antral follicles present in the ovaries of 22–25 day old control (+/+), heterozygous (+/−), and homozygous (−/−) PGRMC1 mice. The percentage of atretic follicles is shown at the base of each bar graph (Data from Pru and Peluso, unpublished). (C) Is a model illustrating a mechanism through which progesterone (P4) activates a PGRMC1-dependent cascade that regulates the events that initiate entry into the cell cycle. Note that a numbered blue call out box identifies the sequence of events in this mechanism and the gray triangle symbolizes increasing P4 levels within the cell. ^*p < 0.05.