The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology

•PGRMC1 is a putative progesterone receptor with many reported cellular functions.•A recently published crystal structure of PGRMC1 has revealed significant new insights into the function of this protein.•PGMRC1 is emerging as a potential player in cancer development, progression and response to chemotherapy.

Progesterone receptor membrane component 1 (PGRMC1) is a multi-functional protein with a heme-binding moiety related to that of cytochrome b5, which is a putative progesterone receptor. The recently solved PGRMC1 structure revealed that heme-binding involves coordination by a tyrosinate ion at Y113, and induces dimerization which is stabilized by hydrophobic stacking of heme on adjacent monomers. Dimerization is required for association with cytochrome P450 (cyP450) enzymes, which mediates chemoresistance to doxorubicin and may be responsible for PGRMC1's anti-apoptotic activity. Here we review the multiple attested involvement of PGRMC1 in diverse functions, including regulation of cytochrome P450, steroidogenesis, vesicle trafficking, progesterone signaling and mitotic spindle and cell cycle regulation. Its wide range of biological functions is attested to particularly by its emerging association with cancer and progesterone-responsive female reproductive tissues. PGRMC1 exhibits all the hallmarks of a higher order nexus signal integration hub protein. It appears capable of acting as a detector that integrates information from kinase/phosphatase pathways with heme and CO levels and probably redox status.