PGRMC1 explained

Progesterone receptor membrane component 1 (abbreviated PGRMC1) is a protein which co-purifies with progesterone binding proteins in the liver and ovary.[1] [2] In humans, the PGRMC1 protein is encoded by the PGRMC1 gene.[3]

The sole biochemical function of PGRMC1 is heme-binding.[4] [5] PGRMC1 shares key structural motifs with cytochrome b5.[6] PGRMC1 binds and activates P450 proteins,[7] [8] [9] 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),[10] which regulates cholesterol synthesis.[11]

Expression

PGRMC1 is highly expressed in the liver and kidney in humans[3] with lower expression in the brain, lung, heart, skeletal muscle and pancreas.[3] [12] [13] 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.[14] [15] Microarray analyses have detected PGRMC1 expression in colon, lung and breast tumors.[16] [17] [18]

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.[19] PGRMC1 is expressed in the ovary and corpus luteum, where its expression is induced by progesterone[20] and during pregnancy,[21] respectively. PGRMC1 is expressed in various regions of the brain (hypothalamic area, circumventricular organs, ependymal cells of the lateral ventricles, meninges),[22] including regions known to facilitate lordosis.

Binding to heme and cytochrome P450s

The PGRMC1 yeast homologue, Dap1 (damage associated protein 1), binds heme[23] through a penta-coordinate mechanism.[24] Yeast cells lacking the DAP1 gene are sensitive to DNA damage,[25] and heme-binding is essential for damage resistance.[23] Dap1 is also required for a critical step in cholesterol synthesis in which the P450 protein Erg11/Cyp51 removes a methyl group from lanosterol.[7] [23] [26] 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[7] [23] This function is conserved between the unrelated fungi S. cerevisiae and S. 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.[7] PGRMC1 also activates Cyp21 when the two proteins are co-expressed,[8] 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.[7] Thus, PGRMC1 and its homologues bind and regulate P450 proteins, and it has been likened to “a helping hand for P450 proteins”.[27]

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.[28] 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.

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.[29]

See also

Notes and References

  1. Meyer C, Schmid R, Scriba PC, Wehling M . Purification and partial sequencing of high-affinity progesterone-binding site(s) from porcine liver membranes . European Journal of Biochemistry . 239 . 3 . 726–31 . Aug 1996 . 8774719 . 10.1111/j.1432-1033.1996.0726u.x . free .
  2. Peluso JJ, Romak J, Liu X . 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 . Endocrinology . 149 . 2 . 534–43 . Feb 2008 . 17991724 . 2219306 . 10.1210/en.2007-1050 .
  3. Gerdes D, Wehling M, Leube B, Falkenstein E . Cloning and tissue expression of two putative steroid membrane receptors . Biological Chemistry . 379 . 7 . 907–11 . Jul 1998 . 9705155 . 10.1515/bchm.1998.379.7.907 .
  4. Crudden G, Chitti RE, Craven RJ . 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 . Jan 2006 . 16234411 . 10.1124/jpet.105.094631 . 18928996 .
  5. Ghosh K, Thompson AM, Goldbeck RA, Shi X, Whitman S, Oh E, Zhiwu Z, Vulpe C, Holman TR . Spectroscopic and biochemical characterization of heme binding to yeast Dap1p and mouse PGRMC1p . Biochemistry . 44 . 50 . 16729–36 . Dec 2005 . 16342963 . 2577039 . 10.1021/bi0511585 .
  6. Mifsud W, Bateman A . Membrane-bound progesterone receptors contain a cytochrome b5-like ligand-binding domain . Genome Biology . 3 . 12 . RESEARCH0068 . 2002 . 12537557 . 151170 . 10.1186/gb-2002-3-12-research0068 . free .
  7. Hughes AL, Powell DW, Bard M, Eckstein J, Barbuch R, Link AJ, Espenshade PJ . Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes . Cell Metabolism . 5 . 2 . 143–9 . Feb 2007 . 17276356 . 10.1016/j.cmet.2006.12.009 . free .
  8. Min L, Strushkevich NV, Harnastai IN, Iwamoto H, Gilep AA, Takemori H, Usanov SA, Nonaka Y, Hori H, Vinson GP, Okamoto M . Molecular identification of adrenal inner zone antigen as a heme-binding protein . The FEBS Journal . 272 . 22 . 5832–43 . Nov 2005 . 16279947 . 10.1111/j.1742-4658.2005.04977.x . free .
  9. Min L, Takemori H, Nonaka Y, Katoh Y, Doi J, Horike N, Osamu H, Raza FS, Vinson GP, Okamoto M . 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 . Feb 2004 . 15026187 . 10.1016/j.mce.2003.11.025 . 20640748 .
  10. Suchanek M, Radzikowska A, Thiele C . Photo-leucine and photo-methionine allow identification of protein-protein interactions in living cells . Nature Methods . 2 . 4 . 261–7 . Apr 2005 . 15782218 . 10.1038/nmeth752 . free .
  11. Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, Goldstein JL, Brown MS . Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER . Cell . 110 . 4 . 489–500 . Aug 2002 . 12202038 . 10.1016/S0092-8674(02)00872-3 . free .
  12. Krebs CJ, Jarvis ED, Chan J, Lydon JP, Ogawa S, Pfaff DW . A membrane-associated progesterone-binding protein, 25-Dx, is regulated by progesterone in brain regions involved in female reproductive behaviors . Proceedings of the National Academy of Sciences of the United States of America . 97 . 23 . 12816–21 . Nov 2000 . 11070092 . 18847 . 10.1073/pnas.97.23.12816 . 2000PNAS...9712816K . free .
  13. Selmin O, Lucier GW, Clark GC, Tritscher AM, Vanden Heuvel JP, Gastel JA, Walker NJ, Sutter TR, Bell DA . Isolation and characterization of a novel gene induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver . Carcinogenesis . 17 . 12 . 2609–15 . Dec 1996 . 9006096 . 10.1093/carcin/17.12.2609 . free .
  14. Crudden G, Loesel R, Craven RJ . Overexpression of the cytochrome p450 activator hpr6 (heme-1 domain protein/human progesterone receptor) in tumors . Tumour Biology . 26 . 3 . 142–6 . 2005 . 15970648 . 10.1159/000086485 . 2555270 .
  15. Peluso JJ, Liu X, Saunders MM, Claffey KP, Phoenix K . Regulation of ovarian cancer cell viability and sensitivity to cisplatin by progesterone receptor membrane component-1 . The Journal of Clinical Endocrinology and Metabolism . 93 . 5 . 1592–9 . May 2008 . 18319313 . 10.1210/jc.2007-2771 . free .
  16. Difilippantonio S, Chen Y, Pietas A, Schlüns K, Pacyna-Gengelbach M, Deutschmann N, Padilla-Nash HM, Ried T, Petersen I . Gene expression profiles in human non-small and small-cell lung cancers . European Journal of Cancer . 39 . 13 . 1936–47 . Sep 2003 . 12932674 . 10.1016/S0959-8049(03)00419-2 .
  17. 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. Mark Dewhirst . Gene expression profiles of multiple breast cancer phenotypes and response to neoadjuvant chemotherapy . Clinical Cancer Research . 12 . 3 Pt 1 . 819–26 . Feb 2006 . 16467094 . 10.1158/1078-0432.CCR-05-1447 . free .
  18. Irby RB, Malek RL, Bloom G, Tsai J, Letwin N, Frank BC, Verratti K, Yeatman TJ, Lee NH . Iterative microarray and RNA interference-based interrogation of the SRC-induced invasive phenotype . Cancer Research . 65 . 5 . 1814–21 . Mar 2005 . 15753379 . 10.1158/0008-5472.CAN-04-3609 . free .
  19. Selmin O, Thorne PA, Blachere FM, Johnson PD, Romagnolo DF . Transcriptional activation of the membrane-bound progesterone receptor (mPR) by dioxin, in endocrine-responsive tissues . Molecular Reproduction and Development . 70 . 2 . 166–74 . Feb 2005 . 15570619 . 10.1002/mrd.20090 . 20023746 .
  20. Nilsson EE, Stanfield J, Skinner MK . Interactions between progesterone and tumor necrosis factor-alpha in the regulation of primordial follicle assembly . Reproduction . 132 . 6 . 877–86 . Dec 2006 . 17127748 . 10.1530/REP-06-0045 . 8260010 . free .
  21. Cai Z, Stocco C . Expression and regulation of progestin membrane receptors in the rat corpus luteum . Endocrinology . 146 . 12 . 5522–32 . Dec 2005 . 16123161 . 10.1210/en.2005-0759 . free .
  22. Meffre D, Delespierre B, Gouézou M, Leclerc P, Vinson GP, Schumacher M, Stein DG, Guennoun R . 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 . Jun 2005 . 15934950 . 10.1111/j.1471-4159.2005.03127.x . 10107122 .
  23. Mallory JC, Crudden G, Johnson BL, Mo C, Pierson CA, Bard M, Craven RJ . Dap1p, a heme-binding protein that regulates the cytochrome P450 protein Erg11p/Cyp51p in Saccharomyces cerevisiae . Molecular and Cellular Biology . 25 . 5 . 1669–79 . Mar 2005 . 15713626 . 549369 . 10.1128/MCB.25.5.1669-1679.2005 .
  24. Thompson AM, Reddi AR, Shi X, Goldbeck RA, Moënne-Loccoz P, Gibney BR, Holman TR . Measurement of the heme affinity for yeast dap1p, and its importance in cellular function . Biochemistry . 46 . 50 . 14629–37 . Dec 2007 . 18031064 . 2669782 . 10.1021/bi7013739 .
  25. Hand RA, Jia N, Bard M, Craven RJ . Saccharomyces cerevisiae Dap1p, a novel DNA damage response protein related to the mammalian membrane-associated progesterone receptor . Eukaryotic Cell . 2 . 2 . 306–17 . Apr 2003 . 12684380 . 154842 . 10.1128/EC.2.2.306-317.2003 .
  26. Craven RJ, Mallory JC, Hand RA . Regulation of iron homeostasis mediated by the heme-binding protein Dap1 (damage resistance protein 1) via the P450 protein Erg11/Cyp51 . The Journal of Biological Chemistry . 282 . 50 . 36543–51 . Dec 2007 . 17954932 . 10.1074/jbc.M706770200 . free .
  27. Debose-Boyd RA . A helping hand for cytochrome p450 enzymes . Cell Metabolism . 5 . 2 . 81–3 . Feb 2007 . 17276348 . 10.1016/j.cmet.2007.01.007 . free .
  28. Hand RA, Craven RJ . Hpr6.6 protein mediates cell death from oxidative damage in MCF-7 human breast cancer cells . Journal of Cellular Biochemistry . 90 . 3 . 534–47 . Oct 2003 . 14523988 . 10.1002/jcb.10648 . 24471996 .
  29. Cahill MA, Jazayeri JA, Catalano SM, Toyokuni S, Kovacevic Z, Richardson DR . The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology . Biochim. Biophys. Acta . 1866 . 2 . 339–349 . December 2016 . 27452206 . 10.1016/j.bbcan.2016.07.004 .

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