Biology:PGRMC1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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).[2] 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.[12][13] 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,[13] 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. PGRMC1/25-Dx is expressed in various regions of the brain [hypothalamic area, circumventricular organs, ependymal cells of the lateral ventricles, meninges,[12][22] including regions known to facilitate lordosis.[12]

Binding to heme and cytochrome P450s

The PGRMC1 yeast homologue, Dap1 (damage associated protein 1), binds heme[5][23] through a penta-coordinate mechanism.[5][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][25][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][25] This function is conserved between the unrelated fungi S. cerevisiae and S. pombe. Dap1 also regulates the metabolism of iron in yeast.[26]

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][9] 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.[25] PGRMC1 also promotes survival in human cancer cells after treatment with chemotherapy.[2][4] 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.[28] 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).[2] 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

References

  1. ↑ "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. doi:10.1111/j.1432-1033.1996.0726u.x. PMID 8774719. 
  2. ↑ 2.0 2.1 2.2 2.3 "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. doi:10.1210/en.2007-1050. PMID 17991724. 
  3. ↑ 3.0 3.1 3.2 "Cloning and tissue expression of two putative steroid membrane receptors". Biological Chemistry 379 (7): 907–11. Jul 1998. doi:10.1515/bchm.1998.379.7.907. PMID 9705155. 
  4. ↑ 4.0 4.1 "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. doi:10.1124/jpet.105.094631. PMID 16234411. 
  5. ↑ 5.0 5.1 5.2 "Spectroscopic and biochemical characterization of heme binding to yeast Dap1p and mouse PGRMC1p". Biochemistry 44 (50): 16729–36. Dec 2005. doi:10.1021/bi0511585. PMID 16342963. 
  6. ↑ "Membrane-bound progesterone receptors contain a cytochrome b5-like ligand-binding domain". Genome Biology 3 (12): RESEARCH0068. 2002. doi:10.1186/gb-2002-3-12-research0068. PMID 12537557. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes". Cell Metabolism 5 (2): 143–9. Feb 2007. doi:10.1016/j.cmet.2006.12.009. PMID 17276356. 
  8. ↑ 8.0 8.1 "Molecular identification of adrenal inner zone antigen as a heme-binding protein". The FEBS Journal 272 (22): 5832–43. Nov 2005. doi:10.1111/j.1742-4658.2005.04977.x. PMID 16279947. 
  9. ↑ 9.0 9.1 "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. doi:10.1016/j.mce.2003.11.025. PMID 15026187. 
  10. ↑ "Photo-leucine and photo-methionine allow identification of protein-protein interactions in living cells". Nature Methods 2 (4): 261–7. Apr 2005. doi:10.1038/nmeth752. PMID 15782218. 
  11. ↑ "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. doi:10.1016/S0092-8674(02)00872-3. PMID 12202038. 
  12. ↑ 12.0 12.1 12.2 12.3 "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. doi:10.1073/pnas.97.23.12816. PMID 11070092. Bibcode: 2000PNAS...9712816K. 
  13. ↑ 13.0 13.1 13.2 "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. doi:10.1093/carcin/17.12.2609. PMID 9006096. https://zenodo.org/record/1234303. 
  14. ↑ "Overexpression of the cytochrome p450 activator hpr6 (heme-1 domain protein/human progesterone receptor) in tumors". Tumour Biology 26 (3): 142–6. 2005. doi:10.1159/000086485. PMID 15970648. 
  15. ↑ "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. doi:10.1210/jc.2007-2771. PMID 18319313. 
  16. ↑ "Gene expression profiles in human non-small and small-cell lung cancers". European Journal of Cancer 39 (13): 1936–47. Sep 2003. doi:10.1016/S0959-8049(03)00419-2. PMID 12932674. 
  17. ↑ "Gene expression profiles of multiple breast cancer phenotypes and response to neoadjuvant chemotherapy". Clinical Cancer Research 12 (3 Pt 1): 819–26. Feb 2006. doi:10.1158/1078-0432.CCR-05-1447. PMID 16467094. 
  18. ↑ "Iterative microarray and RNA interference-based interrogation of the SRC-induced invasive phenotype". Cancer Research 65 (5): 1814–21. Mar 2005. doi:10.1158/0008-5472.CAN-04-3609. PMID 15753379. 
  19. ↑ "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. doi:10.1002/mrd.20090. PMID 15570619. 
  20. ↑ "Interactions between progesterone and tumor necrosis factor-alpha in the regulation of primordial follicle assembly". Reproduction 132 (6): 877–86. Dec 2006. doi:10.1530/REP-06-0045. PMID 17127748. 
  21. ↑ "Expression and regulation of progestin membrane receptors in the rat corpus luteum". Endocrinology 146 (12): 5522–32. Dec 2005. doi:10.1210/en.2005-0759. PMID 16123161. 
  22. ↑ "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. doi:10.1111/j.1471-4159.2005.03127.x. PMID 15934950. 
  23. ↑ 23.0 23.1 23.2 23.3 "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. doi:10.1128/MCB.25.5.1669-1679.2005. PMID 15713626. 
  24. ↑ "Measurement of the heme affinity for yeast dap1p, and its importance in cellular function". Biochemistry 46 (50): 14629–37. Dec 2007. doi:10.1021/bi7013739. PMID 18031064. 
  25. ↑ 25.0 25.1 25.2 25.3 "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. doi:10.1128/EC.2.2.306-317.2003. PMID 12684380. 
  26. ↑ 26.0 26.1 "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. doi:10.1074/jbc.M706770200. PMID 17954932. 
  27. ↑ "A helping hand for cytochrome p450 enzymes". Cell Metabolism 5 (2): 81–3. Feb 2007. doi:10.1016/j.cmet.2007.01.007. PMID 17276348. 
  28. ↑ 28.0 28.1 "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. doi:10.1002/jcb.10648. PMID 14523988. 
  29. ↑ "The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology". Biochim. Biophys. Acta 1866 (2): 339–349. December 2016. doi:10.1016/j.bbcan.2016.07.004. PMID 27452206. 




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