PGRMC1

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 PGRMC1 gene.[7]

PGRMC1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPGRMC1, HPR6.6, MPR, progesterone receptor membrane component 1, Dap1, IZA
External IDsOMIM: 300435 MGI: 1858305 HomoloGene: 48457 GeneCards: PGRMC1
Gene location (Human)
Chr.X chromosome (human)[1]
BandXq24Start119,236,245 bp[1]
End119,244,466 bp[1]
RNA expression pattern


More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

10857

53328

Ensembl

ENSG00000101856

ENSMUSG00000006373

UniProt

O00264
Q6IB11

O55022

RefSeq (mRNA)

NM_006667
NM_001282621

NM_016783

RefSeq (protein)

NP_001269550
NP_006658
NP_006658.1

NP_058063

Location (UCSC)Chr X: 119.24 – 119.24 MbChr X: 36.6 – 36.61 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

Expression

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 carcinogen 2,3,7,8-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]

Binding to heme and cytochrome P450s

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]

Roles in signaling and apoptosis

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 Akt protein 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]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000101856 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000006373 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Meyer C, Schmid R, Scriba PC, Wehling M (Aug 1996). "Purification and partial sequencing of high-affinity progesterone-binding site(s) from porcine liver membranes". European Journal of Biochemistry / FEBS. 239 (3): 726–31. doi:10.1111/j.1432-1033.1996.0726u.x. PMID 8774719.
  6. Peluso JJ, Romak J, Liu X (Feb 2008). "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. doi:10.1210/en.2007-1050. PMC 2219306. PMID 17991724.
  7. Gerdes 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. PMID 9705155.
  8. Crudden 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. PMID 16234411.
  9. Ghosh K, Thompson AM, Goldbeck RA, Shi X, Whitman S, Oh E, Zhiwu Z, Vulpe C, Holman TR (Dec 2005). "Spectroscopic and biochemical characterization of heme binding to yeast Dap1p and mouse PGRMC1p". Biochemistry. 44 (50): 16729–36. doi:10.1021/bi0511585. PMC 2577039. PMID 16342963.
  10. Mifsud W, Bateman A (2002). "Membrane-bound progesterone receptors contain a cytochrome b5-like ligand-binding domain". Genome Biology. 3 (12): RESEARCH0068. doi:10.1186/gb-2002-3-12-research0068. PMC 151170. PMID 12537557.
  11. Hughes AL, Powell DW, Bard M, Eckstein J, Barbuch R, Link AJ, Espenshade PJ (Feb 2007). "Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes". Cell Metabolism. 5 (2): 143–9. doi:10.1016/j.cmet.2006.12.009. PMID 17276356.
  12. Min L, Strushkevich NV, Harnastai IN, Iwamoto H, Gilep AA, Takemori H, Usanov SA, Nonaka Y, Hori H, Vinson GP, Okamoto M (Nov 2005). "Molecular identification of adrenal inner zone antigen as a heme-binding protein". The FEBS Journal. 272 (22): 5832–43. doi:10.1111/j.1742-4658.2005.04977.x. PMID 16279947.
  13. Min 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. PMID 15026187.
  14. Suchanek M, Radzikowska A, Thiele C (Apr 2005). "Photo-leucine and photo-methionine allow identification of protein-protein interactions in living cells". Nature Methods. 2 (4): 261–7. doi:10.1038/nmeth752. PMID 15782218.
  15. Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, Goldstein JL, Brown MS (Aug 2002). "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. doi:10.1016/S0092-8674(02)00872-3. PMID 12202038.
  16. Krebs CJ, Jarvis ED, Chan J, Lydon JP, Ogawa S, Pfaff DW (Nov 2000). "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. doi:10.1073/pnas.97.23.12816. PMC 18847. PMID 11070092.
  17. Selmin O, Lucier GW, Clark GC, Tritscher AM, Vanden Heuvel JP, Gastel JA, Walker NJ, Sutter TR, Bell DA (Dec 1996). "Isolation and characterization of a novel gene induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver" (PDF). Carcinogenesis. 17 (12): 2609–15. doi:10.1093/carcin/17.12.2609. PMID 9006096.
  18. Crudden G, Loesel R, Craven RJ (2005). "Overexpression of the cytochrome p450 activator hpr6 (heme-1 domain protein/human progesterone receptor) in tumors". Tumour Biology. 26 (3): 142–6. doi:10.1159/000086485. PMID 15970648.
  19. Peluso JJ, Liu X, Saunders MM, Claffey KP, Phoenix K (May 2008). "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. doi:10.1210/jc.2007-2771. PMID 18319313.
  20. 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. PMID 12932674.
  21. 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 (Feb 2006). "Gene expression profiles of multiple breast cancer phenotypes and response to neoadjuvant chemotherapy". Clinical Cancer Research. 12 (3 Pt 1): 819–26. doi:10.1158/1078-0432.CCR-05-1447. PMID 16467094.
  22. Irby RB, Malek RL, Bloom G, Tsai J, Letwin N, Frank BC, Verratti K, Yeatman TJ, Lee NH (Mar 2005). "Iterative microarray and RNA interference-based interrogation of the SRC-induced invasive phenotype". Cancer Research. 65 (5): 1814–21. doi:10.1158/0008-5472.CAN-04-3609. PMID 15753379.
  23. 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. PMID 15570619.
  24. Nilsson EE, Stanfield J, Skinner MK (Dec 2006). "Interactions between progesterone and tumor necrosis factor-alpha in the regulation of primordial follicle assembly". Reproduction. 132 (6): 877–86. doi:10.1530/REP-06-0045. PMID 17127748.
  25. Cai Z, Stocco C (Dec 2005). "Expression and regulation of progestin membrane receptors in the rat corpus luteum". Endocrinology. 146 (12): 5522–32. doi:10.1210/en.2005-0759. PMID 16123161.
  26. 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. PMID 15934950.
  27. Mallory JC, Crudden G, Johnson BL, Mo C, Pierson CA, Bard M, Craven RJ (Mar 2005). "Dap1p, a heme-binding protein that regulates the cytochrome P450 protein Erg11p/Cyp51p in Saccharomyces cerevisiae". Molecular and Cellular Biology. 25 (5): 1669–79. doi:10.1128/MCB.25.5.1669-1679.2005. PMC 549369. PMID 15713626.
  28. Thompson AM, Reddi AR, Shi X, Goldbeck RA, Moënne-Loccoz P, Gibney BR, Holman TR (Dec 2007). "Measurement of the heme affinity for yeast dap1p, and its importance in cellular function". Biochemistry. 46 (50): 14629–37. doi:10.1021/bi7013739. PMC 2669782. PMID 18031064.
  29. Hand RA, Jia N, Bard M, Craven RJ (Apr 2003). "Saccharomyces cerevisiae Dap1p, a novel DNA damage response protein related to the mammalian membrane-associated progesterone receptor". Eukaryotic Cell. 2 (2): 306–17. doi:10.1128/EC.2.2.306-317.2003. PMC 154842. PMID 12684380.
  30. Craven RJ, Mallory JC, Hand RA (Dec 2007). "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. doi:10.1074/jbc.M706770200. PMID 17954932.
  31. Debose-Boyd RA (Feb 2007). "A helping hand for cytochrome p450 enzymes". Cell Metabolism. 5 (2): 81–3. doi:10.1016/j.cmet.2007.01.007. PMID 17276348.
  32. Hand 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. PMID 14523988.
  33. 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. PMID 27452206.


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