Evidence for a genomic mechanism of action for progesterone receptor membrane component-1

Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in the granulosa and luteal cells of rodent and primate ovaries. Interestingly, its molecular weight as assessed by Western blot is dependent on its cellular localization with a ≈27 kDa form being detected in the cytoplasm and higher molecular weight forms being detected in the nucleus. The higher molecular weight forms of PGRMC1 are sumoylated suggesting that they are involved in regulating gene transcription, since sumoylation of nuclear proteins often is associated with regulation of transcriptional activity of the sumoylated protein.In order to identify a set of candidate genes that are regulated by PGRMC1, a human granulosa/luteal cell line (hGL5 cells) was treated with PGRMC1 siRNA and changes in gene expression monitored by microarray analysis. The microarray analysis revealed that PGRMC1 generally functioned as a repressor of transcription, since depletion of PGRMC1 resulted in a disproportionate increase in the number of transcripts. Moreover, a pathway analysis implicated PGRMC1 in the regulation of apoptosis, which is consistent with PGRMC1’s known biological action. More importantly these results support the concept that PGRMC1 influences gene transcription. Additional studies reveal that progesterone (P4) acting through a PGRMC1-dependent mechanism suppresses the activity of the transcription factor, Tcf/Lef, thereby identifying one molecular pathway through which P4–PGRMC1 can regulate gene transcription and ultimately apoptosis.

An image of an in situ proximity assay demonstrating that PGRMC1 and Sumo1 directly interact and are presumably covalently coupled, as revealed by the red dots. The nuclei are stained with DAPI and are shown in blue. Note that most of the sumoylated PGRMC1 is localized to the nuclei, although some sumoylated PGRMC1 is in the cytoplasm. These findings are consist with our hypothesis that PGRMC1 is sumoylated in the cytoplasm, then transported to the nucleus where it regulates gene transcription.Figure optionsDownload as PowerPoint slideHighlights
► Progesterone (P4) acts through progesterone receptor membrane component 1 (PGRMC1).
► P4-PGRMC1 interaction regulates gene expression.
► P4-regulatedgene expression inhibits apoptosis of granulosa cells.
► P4-PGRMC1 regulates gene expression by suppressing Tcf/Lef activity.
► This mechanism involves PGRMC1 sumoylation and nuclear localization.