title: The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology.
abstract: 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.
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia. Electronic address: mcahill@csu.edu.au.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cahill
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia.
authors.forename: Jalal A
authors.initials: JA
authors.lastname: Jazayeri
authors.affiliation: Cognition Therapeutics Inc., Pittsburgh, PA 15203, United States.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Catalano
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Zaklina
authors.initials: Z
authors.lastname: Kovacevic
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia. Electronic address: richardson@med.usyd.edu.au.
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
mesh_terms: D002453:Cell Cycle; D049109:Cell Proliferation; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D055503:Protein Multimerization; D011980:Receptors, Progesterone / Q000737:chemistry / Q000502:physiology*; D017480:Receptors, sigma / Q000502:physiology
chemical_list: D008565:Membrane Proteins; C115296:PGRMC1 protein, human; D011980:Receptors, Progesterone; D017480:Receptors, sigma; C106107:sigma-2 receptor
keywords: Cancer; Cytochrome P450; Phosphorylation; SH2-domain; SH3-domain; Signaling