PGRMC1

Progesterone receptor membrane component 1 (abbreviated PGRMC1) is a protein which co-purifies with progesterone binding proteins in the liver and ovary.cite journal | author = Meyer C, Schmid R, Scriba PC, Wehling M | title = Purification and partial sequencing of high-affinity progesterone-binding site(s) from porcine liver membranes | journal = Eur. J. Biochem. | volume = 239 | issue = 3 | pages = 726–31 | year = 1996 | month = August | pmid = 8774719 | url = | doi = 10.1111/j.1432-1033.1996.0726u.x ] cite journal | author = Peluso JJ, Romak J, Liu X | title = Progesterone receptor membrane component-1 (PGRMC1) is the mediator of progesterone's antiapoptotic action in spontaneously immortalized granulosa cells as revealed by PGRMC1 small interfering ribonucleic acid treatment and functional analysis of PGRMC1 mutations | journal = Endocrinology | volume = 149 | issue = 2 | pages = 534–43 | year = 2008 | month = February | pmid = 17991724 | doi = 10.1210/en.2007-1050 | url = ] The sole biochemical function of PGRMC1 is heme-binding.cite journal | author = Crudden G, Chitti RE, Craven RJ | title = Hpr6 (heme-1 domain protein) regulates the susceptibility of cancer cells to chemotherapeutic drugs | journal = J. Pharmacol. Exp. Ther. | volume = 316 | issue = 1 | pages = 448–55 | year = 2006 | month = January | pmid = 16234411 | doi = 10.1124/jpet.105.094631 | url = ] cite journal | author = Ghosh K, Thompson AM, Goldbeck RA, Shi X, Whitman S, Oh E, Zhiwu Z, Vulpe C, Holman TR | title = Spectroscopic and biochemical characterization of heme binding to yeast Dap1p and mouse PGRMC1p | journal = Biochemistry | volume = 44 | issue = 50 | pages = 16729–36 | year = 2005 | month = December | pmid = 16342963 | doi = 10.1021/bi0511585 | url = ] PGRMC1 shares key structural motifs with cytochrome b₅.cite journal | author = Mifsud W, Bateman A | title = Membrane-bound progesterone receptors contain a cytochrome b5-like ligand-binding domain | journal = Genome Biol. | volume = 3 | issue = 12 | pages = RESEARCH0068 | year = 2002 | pmid = 12537557 | pmc = 151170 | url = | doi = 10.1186/gb-2002-3-12-research0068 ] PGRMC1 binds and activates P450 proteins,cite journal | author = Hughes AL, Powell DW, Bard M, Eckstein J, Barbuch R, Link AJ, Espenshade PJ | title = Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes | journal = Cell Metab. | volume = 5 | issue = 2 | pages = 143–9 | year = 2007 | month = February | pmid = 17276356 | doi = 10.1016/j.cmet.2006.12.009 | url = ] cite journal | author = Min L, Strushkevich NV, Harnastai IN, Iwamoto H, Gilep AA, Takemori H, Usanov SA, Nonaka Y, Hori H, Vinson GP, Okamoto M | title = Molecular identification of adrenal inner zone antigen as a heme-binding protein | journal = FEBS J. | volume = 272 | issue = 22 | pages = 5832–43 | year = 2005 | month = November | pmid = 16279947 | doi = 10.1111/j.1742-4658.2005.04977.x | url = ] cite journal | author = Min L, Takemori H, Nonaka Y, Katoh Y, Doi J, Horike N, Osamu H, Raza FS, Vinson GP, Okamoto M | title = Characterization of the adrenal-specific antigen IZA (inner zone antigen) and its role in the steroidogenesis | journal = Mol. Cell. Endocrinol. | volume = 215 | issue = 1-2 | pages = 143–8 | year = 2004 | month = February | pmid = 15026187 | doi = 10.1016/j.mce.2003.11.025 | url = ] which are important in drug, hormone and lipid metabolism. PGRMC1 also binds to PAIR-BP1 (plasminogen activator inhibitor RNA-binding protein-1). 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),cite journal | author = Suchanek M, Radzikowska A, Thiele C | title = Photo-leucine and photo-methionine allow identification of protein-protein interactions in living cells | journal = Nat. Methods | volume = 2 | issue = 4 | pages = 261–7 | year = 2005 | month = April | pmid = 15782218 | doi = 10.1038/nmeth752 | url = ] which regulates cholesterol synthesis.cite journal | author =Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, Goldstein JL, Brown MS | title = Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER | journal = Cell | volume = 110 | issue = 4 | pages = 489–500 | year = 2002 | month = August | pmid = 12202038 | doi = | url = http://linkinghub.elsevier.com/retrieve/pii/S0092867402008723 | issn = ]

Expression

PGRMC1 is highly expressed in the liver and kidney in humanscite journal | author = Gerdes D, Wehling M, Leube B, Falkenstein E | title = Cloning and tissue expression of two putative steroid membrane receptors | journal = Biol. Chem. | volume = 379 | issue = 7 | pages = 907–11 | year = 1998 | month = July | pmid = 9705155 | doi = | url = | issn = ] with lower expression in the brain, lung, heart, skeletal muscle and pancreas.cite journal | author = Krebs CJ, Jarvis ED, Chan J, Lydon JP, Ogawa S, Pfaff DW | title = A membrane-associated progesterone-binding protein, 25-Dx, is regulated by progesterone in brain regions involved in female reproductive behaviors | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 23 | pages = 12816–21 | year = 2000 | month = November | pmid = 11070092 | pmc = 18847 | doi = 10.1073/pnas.97.23.12816 | url = ] cite journal | author = Selmin O, Lucier GW, Clark GC, Tritscher AM, Vanden Heuvel JP, Gastel JA, Walker NJ, Sutter TR, Bell DA | title = Isolation and characterization of a novel gene induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver | journal = Carcinogenesis | volume = 17 | issue = 12 | pages = 2609–15 | year = 1996 | month = December | pmid = 9006096 | url = | doi = 10.1093/carcin/17.12.2609 ] In rodents, PGRMC1 is found in the liver, lung, kidney and brain. PGRMC1 is over-expressed in breast tumors and in cancer cell lines from the colon, thyroid, ovary, lung, and cervix.cite journal | author = Crudden G, Loesel R, Craven RJ | title = Overexpression of the cytochrome p450 activator hpr6 (heme-1 domain protein/human progesterone receptor) in tumors | journal = Tumour Biol. | volume = 26 | issue = 3 | pages = 142–6 | year = 2005 | pmid = 15970648 | doi = 10.1159/000086485 | url = ] cite journal | author = Peluso JJ, Liu X, Saunders MM, Claffey KP, Phoenix K | title = Regulation of ovarian cancer cell viability and sensitivity to cisplatin by progesterone receptor membrane component-1 | journal = J. Clin. Endocrinol. Metab. | volume = 93 | issue = 5 | pages = 1592–9 | year = 2008 | month = May | pmid = 18319313 | doi = 10.1210/jc.2007-2771 | url = ] Microarray analyses have detected PGRMC1 expression in colon, lung and breast tumors.cite journal | author = Difilippantonio S, Chen Y, Pietas A, Schlüns K, Pacyna-Gengelbach M, Deutschmann N, Padilla-Nash HM, Ried T, Petersen I | title = Gene expression profiles in human non-small and small-cell lung cancers | journal = Eur. J. Cancer | volume = 39 | issue = 13 | pages = 1936–47 | year = 2003 | month = September | pmid = 12932674 | url = | doi = 10.1016/S0959-8049(03)00419-2 ] cite journal | author = Dressman HK, Hans C, Bild A, Olson JA, Rosen E, Marcom PK, Liotcheva VB, Jones EL, Vujaskovic Z, Marks J, Dewhirst MW, West M, Nevins JR, Blackwell K | title = Gene expression profiles of multiple breast cancer phenotypes and response to neoadjuvant chemotherapy | journal = Clin. Cancer Res. | volume = 12 | issue = 3 Pt 1 | pages = 819–26 | year = 2006 | month = February | pmid = 16467094 | doi = 10.1158/1078-0432.CCR-05-1447 | url = ] cite journal | author = Irby RB, Malek RL, Bloom G, Tsai J, Letwin N, Frank BC, Verratti K, Yeatman TJ, Lee NH | title = Iterative microarray and RNA interference-based interrogation of the SRC-induced invasive phenotype | journal = Cancer Res. | volume = 65 | issue = 5 | pages = 1814–21 | year = 2005 | month = March | pmid = 15753379 | doi = 10.1158/0008-5472.CAN-04-3609 | url = ]

PGRMC1 expression is induced by the non-genotoxic carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat liver, but this induction is specific to males.cite journal | author = Selmin O, Thorne PA, Blachere FM, Johnson PD, Romagnolo DF | title = Transcriptional activation of the membrane-bound progesterone receptor (mPR) by dioxin, in endocrine-responsive tissues | journal = Mol. Reprod. Dev. | volume = 70 | issue = 2 | pages = 166–74 | year = 2005 | month = February | pmid = 15570619 | doi = 10.1002/mrd.20090 | url = ] PGRMC1 is expressed in the ovary and corpus luteum, where its expression is induced by progesteronecite journal | author = Nilsson EE, Stanfield J, Skinner MK | title = Interactions between progesterone and tumor necrosis factor-alpha in the regulation of primordial follicle assembly | journal = Reproduction | volume = 132 | issue = 6 | pages = 877–86 | year = 2006 | month = December | pmid = 17127748 | doi = 10.1530/REP-06-0045 | url = ] and during pregnancy,cite journal | author = Cai Z, Stocco C | title = Expression and regulation of progestin membrane receptors in the rat corpus luteum | journal = Endocrinology | volume = 146 | issue = 12 | pages = 5522–32 | year = 2005 | month = December | pmid = 16123161 | doi = 10.1210/en.2005-0759 | url = ] respectively. PGRMC1/25-Dx is expressed in various regions of the brain [hypothalamic area, circumventricular organs, ependymal cells of the lateral ventricles, meninges,cite journal | author = Meffre D, Delespierre B, Gouézou M, Leclerc P, Vinson GP, Schumacher M, Stein DG, Guennoun R | title = 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 = J. Neurochem. | volume = 93 | issue = 5 | pages = 1314–26 | year = 2005 | month = June | pmid = 15934950 | doi = 10.1111/j.1471-4159.2005.03127.x | url = ] including regions known to facilitate lordosis.

PGRMC1 binding to heme and P450s is conserved from yeast to humans

The PGRMC1 yeast homologue, Dap1 (damage associated protein 1), binds hemecite journal | author = Mallory JC, Crudden G, Johnson BL, Mo C, Pierson CA, Bard M, Craven RJ | title = Dap1p, a heme-binding protein that regulates the cytochrome P450 protein Erg11p/Cyp51p in Saccharomyces cerevisiae | journal = Mol. Cell. Biol. | volume = 25 | issue = 5 | pages = 1669–79 | year = 2005 | month = March | pmid = 15713626 | pmc = 549369 | doi = 10.1128/MCB.25.5.1669-1679.2005 | url = ] through a penta-coordinate mechanism.cite journal | author = Thompson AM, Reddi AR, Shi X, Goldbeck RA, Moënne-Loccoz P, Gibney BR, Holman TR | title = Measurement of the heme affinity for yeast dap1p, and its importance in cellular function | journal = Biochemistry | volume = 46 | issue = 50 | pages = 14629–37 | year = 2007 | month = December | pmid = 18031064 | doi = 10.1021/bi7013739 | url = ] Yeast cells lacking the DAP1 gene are sensitive to DNA damage,cite journal | author = Hand RA, Jia N, Bard M, Craven RJ | title = Saccharomyces cerevisiae Dap1p, a novel DNA damage response protein related to the mammalian membrane-associated progesterone receptor | journal = Eukaryotic Cell | volume = 2 | issue = 2 | pages = 306–17 | year = 2003 | month = April | pmid = 12684380 | pmc = 154842 | doi = | url = http://ec.asm.org/cgi/pmidlookup?view=long&pmid=12684380 | issn = ] and heme-binding is essential for damage resistance. Dap1 is also required for a critical step in cholesterol synthesis in which the P450 protein Erg11/Cyp51 removes a methyl group from lanosterol.cite journal | author = Craven RJ, Mallory JC, Hand RA | title = Regulation of iron homeostasis mediated by the heme-binding protein Dap1 (damage resistance protein 1) via the P450 protein Erg11/Cyp51 | journal = J. Biol. Chem. | volume = 282 | issue = 50 | pages = 36543–51 | year = 2007 | month = December | pmid = 17954932 | doi = 10.1074/jbc.M706770200 | url = ] cite journal | author = Mallory JC, Crudden G, Johnson BL, Mo C, Pierson CA, Bard M, Craven RJ | title = Dap1p, a heme-binding protein that regulates the cytochrome P450 protein Erg11p/Cyp51p in Saccharomyces cerevisiae | journal = Mol. Cell. Biol. | volume = 25 | issue = 5 | pages = 1669–79 | year = 2005 | month = March | pmid = 15713626 | pmc = 549369 | doi = 10.1128/MCB.25.5.1669-1679.2005 | url = ] 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 This function is conserved between the unrelated fungi Saccharomyces cerevisiae and Schizosaccharomyces pombe. Dap1 also regulates the metabolism of iron in yeast.

In yeast and humans, PGRMC1 binds directly to P450 proteins, including CYP51A1, CYP3A4, CYP7A1 and CYP21A2. PGRMC1 also activates Cyp21 when the two proteins are co-expressed,cite journal | author = Min L, Strushkevich NV, Harnastai IN, Iwamoto H, Gilep AA, Takemori H, Usanov SA, Nonaka Y, Hori H, Vinson GP, Okamoto M | title = Molecular identification of adrenal inner zone antigen as a heme-binding protein | journal = FEBS J. | volume = 272 | issue = 22 | pages = 5832–43 | year = 2005 | month = November | pmid = 16279947 | doi = 10.1111/j.1742-4658.2005.04977.x | url = ] indicating that PGRMC1 promotes progesterone turnover. Just as Dap1 is required for the action of Erg11 in the sythesis of ergosterol in yeast, PGRMC1 regulates the Cyp51-catalyzed demethylation step in human cholesterol synthesis. Thus, PGRMC1 and its homologues bind and regulate P450 proteins, and it has been likened to “a helping hand for P450 proteins”.cite journal | author = Debose-Boyd RA | title = A helping hand for cytochrome p450 enzymes | journal = Cell Metab. | volume = 5 | issue = 2 | pages = 81–3 | year = 2007 | month = February | pmid = 17276348 | doi = 10.1016/j.cmet.2007.01.007 | url = ]

Roles in signaling and apoptosis

The yeast PGRMC1 homologue is required for resistance to damage. PGRMC1 also promotes survival in human cancer cells after treatment with chemotherapy. In contrast, PGRMC1 promotes cell death in cancer cells after oxidative damage.cite journal | author = Hand RA, Craven RJ | title = Hpr6.6 protein mediates cell death from oxidative damage in MCF-7 human breast cancer cells | journal = J. Cell. Biochem. | volume = 90 | issue = 3 | pages = 534–47 | year = 2003 | month = October | pmid = 14523988 | doi = 10.1002/jcb.10648 | url = ] PGRMC1 alters several known survival signaling proteins, including the Akt protein kinase and the cell death-associated protein IκB. 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). However, PAIR-BP1 is not a progesterone binding protein, and the component of the PGRMC1 complex that binds to progesterone is unknown.

References

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