Progesterone receptor membrane component 1 (abbreviated PGRMC1) is a protein which co-purifies with progesterone binding proteins in the liver and ovary.[5][6] In humans, the PGRMC1 protein is encoded by the PGRMC1gene.[7]
The sole biochemical function of PGRMC1 is heme-binding.[8][9] PGRMC1 shares key structural motifs with cytochrome b5.[10] PGRMC1 binds and activates P450 proteins,[11][12][13] which are important in drug, hormone and lipid metabolism. PGRMC1 also binds to PAIR-BP1 (plasminogen activator inhibitor RNA-binding protein-1).[6] However, its expression outside of the reproductive tract and in males suggests multiple functions for the protein. These may include binding to Insig (insulin-induced gene),[14] which regulates cholesterol synthesis.[15]
PGRMC1 is highly expressed in the liver and kidney in humans[7] with lower expression in the brain, lung, heart, skeletal muscle and pancreas.[7][16][17] In rodents, PGRMC1 is found in the liver, lung, kidney and brain.[16][17] PGRMC1 is over-expressed in breast tumors and in cancer cell lines from the colon, thyroid, ovary, lung, and cervix.[18][19]Microarray analyses have detected PGRMC1 expression in colon, lung and breast tumors.[20][21][22]
PGRMC1 expression is induced by the non-genotoxic carcinogen2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat liver,[17] but this induction is specific to males.[23] PGRMC1 is expressed in the ovary and corpus luteum, where its expression is induced by progesterone[24] and during pregnancy,[25] respectively. PGRMC1/25-Dx is expressed in various regions of the brain [hypothalamic area, circumventricular organs, ependymal cells of the lateral ventricles, meninges,[16][26] including regions known to facilitate lordosis.[16]
The PGRMC1 yeast homologue, Dap1 (damage associated protein 1), binds heme[9][27] through a penta-coordinate mechanism.[9][28] Yeast cells lacking the DAP1 gene are sensitive to DNA damage,[29] and heme-binding is essential for damage resistance.[27] Dap1 is also required for a critical step in cholesterol synthesis in which the P450 protein Erg11/Cyp51 removes a methyl group from lanosterol.[11][27][29][30] Erg11/Cyp51 is the target of the azole antifungal drugs. As a result, yeast cells lacking the DAP1 gene are highly sensitive to antifungal drugs[11][27][29] This function is conserved between the unrelated fungi S. cerevisiae and S. pombe. Dap1 also regulates the metabolism of iron in yeast.[30]
In yeast and humans, PGRMC1 binds directly to P450 proteins, including CYP51A1, CYP3A4, CYP7A1 and CYP21A2.[11] PGRMC1 also activates Cyp21 when the two proteins are co-expressed,[12][13] indicating that PGRMC1 promotes progesterone turnover. Just as Dap1 is required for the action of Erg11 in the synthesis of ergosterol in yeast, PGRMC1 regulates the Cyp51-catalyzed demethylation step in human cholesterol synthesis.[11] Thus, PGRMC1 and its homologues bind and regulate P450 proteins, and it has been likened to “a helping hand for P450 proteins”.[31]
The yeast PGRMC1 homologue is required for resistance to damage.[29] PGRMC1 also promotes survival in human cancer cells after treatment with chemotherapy.[6][8] In contrast, PGRMC1 promotes cell death in cancer cells after oxidative damage.[32] PGRMC1 alters several known survival signaling proteins, including the Aktprotein kinase and the cell death-associated protein IκB.[32] Progesterone inhibits apoptosis in immortalized granulosa cells, and this activity requires PGRMC1 and its binding partner, PAIR-BP1 (plasminogen activator inhibitor RNA-binding protein-1).[6] However, PAIR-BP1 is not a progesterone binding protein, and the component of the PGRMC1 complex that binds to progesterone is unknown.
PGRMC1 was originally thought to represent a progesterone receptor of some sort and to bind to progesterone, but subsequently thought has moved towards PGRMC1 acting as a downstream mediator of some other progesterone-binding protein.[33]
^ abcGerdes D, Wehling M, Leube B, Falkenstein E (Jul 1998). "Cloning and tissue expression of two putative steroid membrane receptors". Biological Chemistry. 379 (7): 907–11. doi:10.1515/bchm.1998.379.7.907. PMID9705155.
^ abCrudden G, Chitti RE, Craven RJ (Jan 2006). "Hpr6 (heme-1 domain protein) regulates the susceptibility of cancer cells to chemotherapeutic drugs". The Journal of Pharmacology and Experimental Therapeutics. 316 (1): 448–55. doi:10.1124/jpet.105.094631. PMID16234411. S2CID18928996.
^ abMin L, Takemori H, Nonaka Y, Katoh Y, Doi J, Horike N, Osamu H, Raza FS, Vinson GP, Okamoto M (Feb 2004). "Characterization of the adrenal-specific antigen IZA (inner zone antigen) and its role in the steroidogenesis". Molecular and Cellular Endocrinology. 215 (1–2): 143–8. doi:10.1016/j.mce.2003.11.025. PMID15026187. S2CID20640748.
^Difilippantonio S, Chen Y, Pietas A, Schlüns K, Pacyna-Gengelbach M, Deutschmann N, Padilla-Nash HM, Ried T, Petersen I (Sep 2003). "Gene expression profiles in human non-small and small-cell lung cancers". European Journal of Cancer. 39 (13): 1936–47. doi:10.1016/S0959-8049(03)00419-2. PMID12932674.
^Selmin O, Thorne PA, Blachere FM, Johnson PD, Romagnolo DF (Feb 2005). "Transcriptional activation of the membrane-bound progesterone receptor (mPR) by dioxin, in endocrine-responsive tissues". Molecular Reproduction and Development. 70 (2): 166–74. doi:10.1002/mrd.20090. PMID15570619. S2CID20023746.
^Meffre D, Delespierre B, Gouézou M, Leclerc P, Vinson GP, Schumacher M, Stein DG, Guennoun R (Jun 2005). "The membrane-associated progesterone-binding protein 25-Dx is expressed in brain regions involved in water homeostasis and is up-regulated after traumatic brain injury". Journal of Neurochemistry. 93 (5): 1314–26. doi:10.1111/j.1471-4159.2005.03127.x. PMID15934950. S2CID10107122.
^ abHand RA, Craven RJ (Oct 2003). "Hpr6.6 protein mediates cell death from oxidative damage in MCF-7 human breast cancer cells". Journal of Cellular Biochemistry. 90 (3): 534–47. doi:10.1002/jcb.10648. PMID14523988. S2CID24471996.
^Cahill MA, Jazayeri JA, Catalano SM, Toyokuni S, Kovacevic Z, Richardson DR (December 2016). "The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology". Biochim. Biophys. Acta. 1866 (2): 339–349. doi:10.1016/j.bbcan.2016.07.004. PMID27452206.