Membrane progesterone receptor expression in mammalian tissues: a review of regulation and physiological implications

Abstract

The recent discovery of a novel, membrane localized progestin receptor (mPR) unrelated to the classical progesterone receptor (PR) in fishes and its subsequent identification in mammals suggests a potential mediator of non-traditional progestin actions, particularly in tissues where PR is absent. While early studies on mPR focused on final oocyte maturation in fishes, more current studies have examined mPRs in multiple mammalian systems in both reproductive and non-reproductive tissues as well as in diseased tissues. Here we review the current data on mPR in mammalian systems including male and female reproductive tracts, liver, neuroendocrine tissues, the immune system and breast and ovarian cancer. We also provide new data demonstrating mPR expression in the RAW 264.7 immune cell line and bone marrow-derived macrophages as well as mPR expression and downstream gene regulation in ovarian cancer cells.

Figure 1

Expression of mPRs in murine macrophages. A. PCR products amplified from the RAW 264.7 cell line (R) or bone marrow-derived macrophages (B) with the indicated mPR primers with or without recerse transcriptase. B. Western blot analysis of mPRα protein expression in RAW 264.7 or bone marrow-derived macrophages. Anti-mPRα antibody kindly provided by Dr. Peter Thomas (University of Texas Austin).

Figure 2

A. Quantitative-PCR confirmed that the SKOV-3 and ES-2 ovarian cancer cell lines positively express mRNA of each membrane-progesterone receptor (mPR) isoform (−α, −β, −γ) (mean ± SD, n = 4). Relative to control MCF-7 breast cancer cells, SKOV-3 and ES-2 cells express minimal amounts of nuclear progesterone receptor (PR) mRNA. B. Targeted screening of 84 cancer pathway related genes (Human Cancer PathwayFinder™, RT² Profiler™ PCR Array, SABiosciences™) in SKOV-3 cells treated with progesterone (50 nM) for 24 hours revealed a greater than 1.5-fold increase in the expression of 23 distinct gene targets. (note: no genes demonstrated a greater than 0.5-fold decrease in expression.)

Figure 3

The membrane-progesterone receptor (mPR) independently activates two distinct signaling pathways in the SKOV-3 and ES-2 ovarian cancer cell lines. A. Progesterone augmented cAMP levels increase cyclic AMP response element (CRE) transcriptional activity. B. Progesterone-stimulated mPRs activate the JNK1/2 and p38 MAPKs and increase BAX gene expression [69]. The mPR may activate JNK1/2 and p38 by directly stimulating ASK1 via the MAPK-GPCR scaffolding protein β-arrestin. Additionally, mPR-mediated JNK1/2 activity may stimulate BAX gene expression via the p53 tumor suppressor protein.