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Progesterone receptor

PDB rendering based on 1a28.
Available structures
1a28, 1e3k, 1sqn, 1sr7, 1zuc, 2c7a, 2ovh, 2ovm
Identifiers
Symbols PGR; NR3C3; PR
External IDs OMIM607311 MGI97567 HomoloGene713 GeneCards: PGR Gene
RNA expression pattern
PBB GE PGR 208305 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5241 18667
Ensembl ENSG00000082175 ENSMUSG00000031870
UniProt P06401 Q8BW69
RefSeq (mRNA) NM_000926 NM_008829
RefSeq (protein) NP_000917 NP_032855
Location (UCSC) Chr 11:
100.41 - 100.51 Mb
Chr 9:
8.86 - 8.93 Mb
PubMed search [1] [2]

The progesterone receptor (PR) also known as NR3C3 (nuclear receptor subfamily 3, group C, member 3), is an intracellular steroid receptor that specifically binds progesterone. PR is encoded by a single gene PGR residing on chromosome 11q22, it has two main forms, A and B, that differ in their molecular weight.[1][2][3]

Contents

Structure

Like all steroid receptors, the progesterone receptor has an amino and a carboxyl terminal, and between them the regulatory domain, a DNA binding domain, the hinge section, and the hormone binding domain. A special transcription activation function (TAF), called TAF-3, is present in the progesterone receptor-B, in a B-upstream segment (BUS) at the amino acid terminal. This segment is not present in the receptor-A.

Isoforms

As demonstrated in progesterone receptor-deficient mice, the physiological effects of progesterone depend completely on the presence of the human progesterone receptor (hPR), a member of the steroid-receptor superfamily of nuclear receptors. The single-copy human (hPR) gene uses separate promoters and translational start sites to produce two isoforms, hPR-A and -B, which are identical except for an additional 165 amino acids present only in the N terminus of hPR-B.[4] Although hPR-B shares many important structural domains as hPR-A, they are in fact two functionally distinct transcription factors, mediating their own response genes and physiological effects with little overlap. Selective ablation of PR-A in a mouse model, resulting in exclusive production of PR-B, unexpectedly revealed that PR-B contributes to, rather than inhibits, epithelial cell proliferation both in response to estrogen alone and in the presence of progesterone and estrogen. These results suggest that in the uterus, the PR-A isoform is necessary to oppose estrogen-induced proliferation as well as PR-B-dependent proliferation.

Functional Polymorphisms

Six variable sites, including four polymorphisms and five common haplotypes have been identified in the human PR gene .[5] One promoter region polymorphism, +331G/A, creates a unique transcription start site. Biochemical assays showed that the +331G/A polymorphism increases transcription of the PR gene, favoring production of hPR-B in an Ishikawa endometrial cancer cell line.[6]

Several studies have now shown no association between progesterone receptor gene +331G/A polymorphisms and breast or endometrial cancers.[7][8] However, these follow-up studies lacked the sample size and statistical power to make any definitive conclusions, due to the rarity of the +331A SNP. It is currently unknown which if any polymorphisms in this receptor is of significance to cancer.

Function

Estrogen is necessary to induce the progesterone receptors. When no binding hormone is present the carboxyl terminal inhibits transcription. Binding to a hormone induces a structural change that removes the inhibitory action. Progesterone antagonists prevent the structural reconfiguration.

After progesterone binds to the receptor, restructuring with dimerization follows and the complex enters the nucleus and binds to DNA. There transcription takes place, resulting in formation of messenger RNA that is translated by ribosomes to produce specific proteins.

Interactions

Progesterone receptor has been shown to interact with Nuclear receptor co-repressor 2,[9] UBE3A[10] and KLF9.[11]

See also

References

  1. ^ Gadkar-Sable S, Shah C, Rosario G, Sachdeva G, Puri C (2005). "Progesterone receptors: various forms and functions in reproductive tissues". Front. Biosci. 10: 2118–30. doi:10.2741/1685. PMID 15970482.  
  2. ^ Kase, Nathan G.; Speroff, Leon; Glass, Robert L. (1999). Clinical gynecologic endocrinology and infertility. Hagerstown, MD: Lippincott Williams & Wilkins. ISBN 0-683-30379-1.  
  3. ^ Fritz, Marc A.; Speroff, Leon (2005). Clinical gynecologic endocrinology and infertility. Hagerstown, MD: Lippincott Williams & Wilkins. ISBN 0-7817-4795-3.  
  4. ^ Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, Chambon P (1990). "Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B". Embo J. 9 (5): 1603–14. PMID 2328727. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=2328727.  
  5. ^ Terry KL, De Vivo I, Titus-Ernstoff L, Sluss PM, Cramer DW (March 2005). "Genetic variation in the progesterone receptor gene and ovarian cancer risk". Am. J. Epidemiol. 161 (5): 442–51. doi:10.1093/aje/kwi064. PMID 15718480.  
  6. ^ De Vivo I, Huggins GS, Hankinson SE, Lescault PJ, Boezen M, Colditz GA, Hunter DJ (September 2002). "A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk". Proc. Natl. Acad. Sci. U.S.A. 99 (19): 12263–8. doi:10.1073/pnas.192172299. PMID 12218173.  
  7. ^ Feigelson HS, Rodriguez C, Jacobs EJ, Diver WR, Thun MJ, Calle EE (2004). "No association between the progesterone receptor gene +331G/A polymorphism and breast cancer". Cancer Epidemiol. Biomarkers Prev. 13 (6): 1084–5. PMID 15184270.  
  8. ^ Dossus L, Canzian F, Kaaks R, Boumertit A, Weiderpass E (2006). "No association between progesterone receptor gene +331G/A polymorphism and endometrial cancer". Cancer Epidemiol. Biomarkers Prev. 15 (7): 1415–6. doi:10.1158/1055-9965.EPI-06-0215. PMID 16835347.  
  9. ^ Giangrande, P H; Kimbrel E A, Edwards D P, McDonnell D P (May. 2000). "The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding". Mol. Cell. Biol. (UNITED STATES) 20 (9): 3102–15. ISSN 0270-7306. PMID 10757795.  
  10. ^ Nawaz, Z; Lonard D M, Smith C L, Lev-Lehman E, Tsai S Y, Tsai M J, O'Malley B W (Feb. 1999). "The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily". Mol. Cell. Biol. (UNITED STATES) 19 (2): 1182–9. ISSN 0270-7306. PMID 9891052.  
  11. ^ Zhang, Xue-Lian; Zhang Daying, Michel Frank J, Blum Jason L, Simmen Frank A, Simmen Rosalia C M (Jun. 2003). "Selective interactions of Kruppel-like factor 9/basic transcription element-binding protein with progesterone receptor isoforms A and B determine transcriptional activity of progesterone-responsive genes in endometrial epithelial cells". J. Biol. Chem. (United States) 278 (24): 21474–82. doi:10.1074/jbc.M212098200. ISSN 0021-9258. PMID 12672823.  

Further reading

  • Butnor KJ, Burchette JL, Robboy SJ (2002). "Progesterone receptor activity in leiomyomatosis peritonealis disseminata.". Int. J. Gynecol. Pathol. 18 (3): 259–64. PMID 12090595.  
  • Leonhardt SA, Boonyaratanakornkit V, Edwards DP (2004). "Progesterone receptor transcription and non-transcription signaling mechanisms.". Steroids 68 (10-13): 761–70. doi:10.1016/S0039-128X(03)00129-6. PMID 14667966.  
  • Conneely OM, Mulac-Jericevic B, Lydon JP (2004). "Progesterone-dependent regulation of female reproductive activity by two distinct progesterone receptor isoforms.". Steroids 68 (10-13): 771–8. doi:10.1016/S0039-128X(03)00126-0. PMID 14667967.  
  • Bagchi MK, Tsai SY, Tsai MJ, O'Malley BW (1992). "Ligand and DNA-dependent phosphorylation of human progesterone receptor in vitro.". Proc. Natl. Acad. Sci. U.S.A. 89 (7): 2664–8. doi:10.1073/pnas.89.7.2664. PMID 1557371.  
  • Kastner P, Krust A, Turcotte B, et al. (1990). "Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B.". Embo J. 9 (5): 1603–14. PMID 2328727.  
  • Guiochon-Mantel A, Loosfelt H, Lescop P, et al. (1989). "Mechanisms of nuclear localization of the progesterone receptor: evidence for interaction between monomers.". Cell 57 (7): 1147–54. doi:10.1016/0092-8674(89)90052-4. PMID 2736623.  
  • Misrahi M, Atger M, d'Auriol L, et al. (1987). "Complete amino acid sequence of the human progesterone receptor deduced from cloned cDNA.". Biochem. Biophys. Res. Commun. 143 (2): 740–8. doi:10.1016/0006-291X(87)91416-1. PMID 3551956.  
  • Fernandez MD, Carter GD, Palmer TN (1983). "The interaction of canrenone with oestrogen and progesterone receptors in human uterine cytosol.". British journal of clinical pharmacology 15 (1): 95–101. PMID 6849751.  
  • Oñate SA, Tsai SY, Tsai MJ, O'Malley BW (1995). "Sequence and characterization of a coactivator for the steroid hormone receptor superfamily.". Science 270 (5240): 1354–7. doi:10.1126/science.270.5240.1354. PMID 7481822.  
  • Zhang Y, Beck CA, Poletti A, et al. (1995). "Identification of phosphorylation sites unique to the B form of human progesterone receptor. In vitro phosphorylation by casein kinase II.". J. Biol. Chem. 269 (49): 31034–40. PMID 7983041.  
  • Mansour I, Reznikoff-Etievant MF, Netter A (1995). "No evidence for the expression of the progesterone receptor on peripheral blood lymphocytes during pregnancy.". Hum. Reprod. 9 (8): 1546–9. PMID 7989520.  
  • Kalkhoven E, Wissink S, van der Saag PT, van der Burg B (1996). "Negative interaction between the RelA(p65) subunit of NF-kappaB and the progesterone receptor.". J. Biol. Chem. 271 (11): 6217–24. doi:10.1074/jbc.271.11.6217. PMID 8626413.  
  • Wang JD, Zhu JB, Fu Y, et al. (1996). "Progesterone receptor immunoreactivity at the maternofetal interface of first trimester pregnancy: a study of the trophoblast population.". Hum. Reprod. 11 (2): 413–9. PMID 8671234.  
  • Thénot S, Henriquet C, Rochefort H, Cavaillès V (1997). "Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1.". J. Biol. Chem. 272 (18): 12062–8. doi:10.1074/jbc.272.18.12062. PMID 9115274.  
  • Jenster G, Spencer TE, Burcin MM, et al. (1997). "Steroid receptor induction of gene transcription: a two-step model.". Proc. Natl. Acad. Sci. U.S.A. 94 (15): 7879–84. doi:10.1073/pnas.94.15.7879. PMID 9223281.  
  • Shanker YG, Sharma SC, Rao AJ (1997). "Expression of progesterone receptor mRNA in the first trimester human placenta.". Biochem. Mol. Biol. Int. 42 (6): 1235–40. PMID 9305541.  
  • Richer JK, Lange CA, Wierman AM, et al. (1998). "Progesterone receptor variants found in breast cells repress transcription by wild-type receptors.". Breast Cancer Res. Treat. 48 (3): 231–41. doi:10.1023/A:1005941117247. PMID 9598870.  
  • Williams SP, Sigler PB (1998). "Atomic structure of progesterone complexed with its receptor.". Nature 393 (6683): 392–6. doi:10.1038/30775. PMID 9620806.  
  • Boonyaratanakornkit V, Melvin V, Prendergast P, et al. (1998). "High-mobility group chromatin proteins 1 and 2 functionally interact with steroid hormone receptors to enhance their DNA binding in vitro and transcriptional activity in mammalian cells.". Mol. Cell. Biol. 18 (8): 4471–87. PMID 9671457.  
  • Nawaz Z, Lonard DM, Smith CL, et al. (1999). "The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily.". Mol. Cell. Biol. 19 (2): 1182–9. PMID 9891052.  

External links

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