Progesterone receptor

2018-11-16T17:34:04Z

2A0C:5BC0:40:1404:78FA:4451:D3E9:D1D8: Incorrect info, PR-C was removed. The corresponding literature does not have any mention of PR-C. Also it was previously believed that there was a third isoform, but now shown to be incorrect.

{{Infobox gene}}

The '''progesterone receptor''' ('''PR'''), also known as '''NR3C3''' or [[nuclear receptor]] subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone [[progesterone]].

In humans, PR is encoded by a single ''PGR'' [[gene]] residing on [[chromosome 11]]q22,<ref name="pmid3551956">{{cite journal | vauthors = Misrahi M, Atger M, d'Auriol L, Loosfelt H, Meriel C, Fridlansky F, Guiochon-Mantel A, Galibert F, Milgrom E | title = Complete amino acid sequence of the human progesterone receptor deduced from cloned cDNA | journal = Biochemical and Biophysical Research Communications | volume = 143 | issue = 2 | pages = 740–8 | date = March 1987 | pmid = 3551956 | doi = 10.1016/0006-291X(87)91416-1 }}</ref><ref name="pmid3472240">{{cite journal | vauthors = Law ML, Kao FT, Wei Q, Hartz JA, Greene GL, Zarucki-Schulz T, Conneely OM, Jones C, Puck TT, O'Malley BW | title = The progesterone receptor gene maps to human chromosome band 11q13, the site of the mammary oncogene int-2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 9 | pages = 2877–81 | date = May 1987 | pmid = 3472240 | pmc = 304763 | doi = 10.1073/pnas.84.9.2877 }}</ref><ref>[http://may2009.archive.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000082175 ensembl.org, Gene: ESR1 (ENSG00000091831)]</ref> it has two isoforms, [[progesterone receptor A|PR-A]] and [[progesterone receptor B|PR-B]], that differ in their molecular weight.<ref name="pmid15970482">{{cite journal | vauthors = Gadkar-Sable S, Shah C, Rosario G, Sachdeva G, Puri C | title = Progesterone receptors: various forms and functions in reproductive tissues | journal = Frontiers in Bioscience | volume = 10 | issue = | pages = 2118–30 | year = 2005 | pmid = 15970482 | doi = 10.2741/1685 }}</ref><ref name="isbn0-683-30379-1">{{cite book | last1 = Kase | first1 = Nathan G. | last2 = Speroff | first2 = Leon | last3 = Glass | first3 = Robert L. | name-list-format = vanc | title = Clinical gynecologic endocrinology and infertility | publisher = Lippincott Williams & Wilkins | location = Hagerstown, MD | year = 1999 | pages = | isbn = 0-683-30379-1 | oclc = | doi = }}</ref><ref name="isbn0-7817-4795-3">{{cite book | last1 = Fritz | first1 = Marc A. | last2 = Speroff | first2 = Leon | name-list-format = vanc | title = Clinical gynecologic endocrinology and infertility | publisher = Lippincott Williams & Wilkins | location = Hagerstown, MD | year = 2005 | pages = | isbn = 0-7817-4795-3 }}</ref> The PR-B is the positive regulator of the effects of progesterone, while PR-A serve to antagonize the effects of PR-B.<ref name="FalconeHurd2013">{{cite book|author1=Tommaso Falcone|author2=William W. Hurd|title=Clinical Reproductive Medicine and Surgery: A Practical Guide|url=https://books.google.com/books?id=TAYnR1b8jRkC&pg=PA39|date=22 May 2013|publisher=Springer Science & Business Media|isbn=978-1-4614-6837-0|pages=39–}}</ref>

== Function ==
[[Progesterone]] is necessary to induce the progesterone receptors. When no binding hormone is present the carboxyl terminal inhibits [[Transcription (genetics)|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 [[protein dimer|dimer]]ization 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 [[ribosome]]s to produce specific proteins.

==Structure==
{{Pfam box |Symbol = Progest_rcpt_N |Name = Progesterone receptor, N-terminal |Pfam = PF02161 |InterPro = IPR000128 |PROSITE = |PDB = }}

In common with other steroid receptors, the progesterone receptor has a [[N-terminus|N-terminal]] regulatory domain, a [[DNA binding domain]], a hinge section, and a [[C-terminus|C-terminal]] ligand 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==
{{Main|Progesterone receptor A|Progesterone receptor B|Progesterone receptor C}}
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.<ref name="pmid2328727">{{cite journal | vauthors = Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, Chambon P | title = Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B | journal = The EMBO Journal | volume = 9 | issue = 5 | pages = 1603–14 | date = May 1990 | pmid = 2328727 | pmc = 551856 | doi = }}</ref> Although hPR-B shares many important structural domains with 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 .<ref name="pmid15718480">{{cite journal | vauthors = Terry KL, De Vivo I, Titus-Ernstoff L, Sluss PM, Cramer DW | title = Genetic variation in the progesterone receptor gene and ovarian cancer risk | journal = American Journal of Epidemiology | volume = 161 | issue = 5 | pages = 442–51 | date = March 2005 | pmid = 15718480 | pmc = 1380205 | doi = 10.1093/aje/kwi064 }}</ref> 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.<ref name="pmid12218173">{{cite journal | vauthors = De Vivo I, Huggins GS, Hankinson SE, Lescault PJ, Boezen M, Colditz GA, Hunter DJ | title = A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 19 | pages = 12263–8 | date = September 2002 | pmid = 12218173 | pmc = 129433 | doi = 10.1073/pnas.192172299 }}</ref>

Several studies have now shown no association between progesterone receptor gene +331G/A polymorphisms and breast or endometrial cancers.<ref name="pmid15184270">{{cite journal | vauthors = Feigelson HS, Rodriguez C, Jacobs EJ, Diver WR, Thun MJ, Calle EE | title = No association between the progesterone receptor gene +331G/A polymorphism and breast cancer | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 13 | issue = 6 | pages = 1084–5 | date = June 2004 | pmid = 15184270 | doi = }}</ref><ref name="pmid16835347">{{cite journal | vauthors = Dossus L, Canzian F, Kaaks R, Boumertit A, Weiderpass E | title = No association between progesterone receptor gene +331G/A polymorphism and endometrial cancer | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 15 | issue = 7 | pages = 1415–6 | date = July 2006 | pmid = 16835347 | doi = 10.1158/1055-9965.EPI-06-0215 }}</ref> 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 are of significance to cancer.

==Biological role==
Knockout mice of the PR have been found to have severely impaired [[lobuloalveolar]] development of the [[mammary gland]]s<ref name="pmid22844349">{{cite journal | vauthors = Macias H, Hinck L | title = Mammary gland development | journal = Wiley Interdisciplinary Reviews: Developmental Biology | volume = 1 | issue = 4 | pages = 533–57 | year = 2012 | pmid = 22844349 | pmc = 3404495 | doi = 10.1002/wdev.35 }}</ref> as well as delayed but otherwise normal mammary ductal development at [[puberty]].<ref name="HiltonGraham2015">{{cite journal | vauthors = Hilton HN, Graham JD, Clarke CL | title = Minireview: Progesterone Regulation of Proliferation in the Normal Human Breast and in Breast Cancer: A Tale of Two Scenarios? | journal = Molecular Endocrinology | volume = 29 | issue = 9 | pages = 1230–42 | date = September 2015 | pmid = 26266959 | doi = 10.1210/me.2015-1152 }}</ref><ref name="pmid23705924">{{cite journal | vauthors = Aupperlee MD, Leipprandt JR, Bennett JM, Schwartz RC, Haslam SZ | title = Amphiregulin mediates progesterone-induced mammary ductal development during puberty | journal = Breast Cancer Research | volume = 15 | issue = 3 | pages = R44 | year = 2013 | pmid = 23705924 | pmc = 3738150 | doi = 10.1186/bcr3431 }}</ref>

==Ligands==

===Agonists===
* [[Endogenous]] [[progestogen]]s (e.g., [[progesterone]])
* [[Synthetic compound|Synthetic]] [[progestogen]]s (e.g., [[norethisterone]], [[levonorgestrel]], [[medroxyprogesterone acetate]], [[megestrol acetate]], [[dydrogesterone]], [[drospirenone]])

===Mixed===
* [[Selective progesterone receptor modulator]]s (e.g., [[ulipristal acetate]], [[telapristone acetate]], [[vilaprisan]], [[asoprisnil]], [[asoprisnil ecamate]])<ref name="pmid24291072">{{cite journal | vauthors = Knutson TP, Lange CA | title = Tracking progesterone receptor-mediated actions in breast cancer | journal = Pharmacology & Therapeutics | volume = 142 | issue = 1 | pages = 114–25 | date = April 2014 | pmid = 24291072 | doi = 10.1016/j.pharmthera.2013.11.010 | pmc=3943696}}</ref>

===Antagonists===
* [[Antiprogestogen]]s (e.g., [[mifepristone]], [[aglepristone]], [[onapristone]], [[lonaprisan]], [[lilopristone]], [[toripristone]])<ref name="pmid24291072" />

== Interactions ==

Progesterone receptor has been shown to [[Protein-protein interaction|interact]] with:
* [[KLF9]],<ref name="pmid12672823">{{cite journal | vauthors = Zhang XL, Zhang D, Michel FJ, Blum JL, Simmen FA, Simmen RC | title = 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 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 24 | pages = 21474–82 | date = June 2003 | pmid = 12672823 | doi = 10.1074/jbc.M212098200 }}</ref>
* [[Nuclear receptor co-repressor 2]],<ref name="pmid10757795">{{cite journal | vauthors = Giangrande PH, Kimbrel EA, Edwards DP, McDonnell DP | title = The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding | journal = Molecular and Cellular Biology | volume = 20 | issue = 9 | pages = 3102–15 | date = May 2000 | pmid = 10757795 | pmc = 85605 | doi = 10.1128/MCB.20.9.3102-3115.2000 }}</ref> and
* [[UBE3A]].<ref name="pmid9891052">{{cite journal | vauthors = Nawaz Z, Lonard DM, Smith CL, Lev-Lehman E, Tsai SY, Tsai MJ, O'Malley BW | title = The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily | journal = Molecular and Cellular Biology | volume = 19 | issue = 2 | pages = 1182–9 | date = February 1999 | pmid = 9891052 | pmc = 116047 | doi = 10.1128/mcb.19.2.1182}}</ref>

== See also ==
* [[Membrane progesterone receptor]]
* [[Selective progesterone receptor modulator]]
* [[Phytoprogestogen]]

== References ==
{{Reflist|2}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Butnor KJ, Burchette JL, Robboy SJ | title = Progesterone receptor activity in leiomyomatosis peritonealis disseminata | journal = International Journal of Gynecological Pathology | volume = 18 | issue = 3 | pages = 259–64 | date = July 1999 | pmid = 12090595 | doi = 10.1097/00004347-199907000-00012 }}
* {{cite journal | vauthors = Leonhardt SA, Boonyaratanakornkit V, Edwards DP | title = Progesterone receptor transcription and non-transcription signaling mechanisms | journal = Steroids | volume = 68 | issue = 10–13 | pages = 761–70 | date = November 2003 | pmid = 14667966 | doi = 10.1016/S0039-128X(03)00129-6 }}
* {{cite journal | vauthors = Conneely OM, Mulac-Jericevic B, Lydon JP | title = Progesterone-dependent regulation of female reproductive activity by two distinct progesterone receptor isoforms | journal = Steroids | volume = 68 | issue = 10–13 | pages = 771–8 | date = November 2003 | pmid = 14667967 | doi = 10.1016/S0039-128X(03)00126-0 }}
* {{cite journal | vauthors = Bagchi MK, Tsai SY, Tsai MJ, O'Malley BW | title = Ligand and DNA-dependent phosphorylation of human progesterone receptor in vitro | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 7 | pages = 2664–8 | date = April 1992 | pmid = 1557371 | pmc = 48722 | doi = 10.1073/pnas.89.7.2664 }}
* {{cite journal | vauthors = Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, Chambon P | title = Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B | journal = The EMBO Journal | volume = 9 | issue = 5 | pages = 1603–14 | date = May 1990 | pmid = 2328727 | pmc = 551856 | doi = }}
* {{cite journal | vauthors = Guiochon-Mantel A, Loosfelt H, Lescop P, Sar S, Atger M, Perrot-Applanat M, Milgrom E | title = Mechanisms of nuclear localization of the progesterone receptor: evidence for interaction between monomers | journal = Cell | volume = 57 | issue = 7 | pages = 1147–54 | date = June 1989 | pmid = 2736623 | doi = 10.1016/0092-8674(89)90052-4 }}
* {{cite journal | vauthors = Fernandez MD, Carter GD, Palmer TN | title = The interaction of canrenone with oestrogen and progesterone receptors in human uterine cytosol | journal = British Journal of Clinical Pharmacology | volume = 15 | issue = 1 | pages = 95–101 | date = January 1983 | pmid = 6849751 | pmc = 1427833 | doi = 10.1111/j.1365-2125.1983.tb01470.x }}
* {{cite journal | vauthors = Oñate SA, Tsai SY, Tsai MJ, O'Malley BW | title = Sequence and characterization of a coactivator for the steroid hormone receptor superfamily | journal = Science | volume = 270 | issue = 5240 | pages = 1354–7 | date = November 1995 | pmid = 7481822 | doi = 10.1126/science.270.5240.1354 }}
* {{cite journal | vauthors = Zhang Y, Beck CA, Poletti A, Edwards DP, Weigel NL | title = Identification of phosphorylation sites unique to the B form of human progesterone receptor. In vitro phosphorylation by casein kinase II | journal = The Journal of Biological Chemistry | volume = 269 | issue = 49 | pages = 31034–40 | date = December 1994 | pmid = 7983041 | doi = }}
* {{cite journal | vauthors = Mansour I, Reznikoff-Etievant MF, Netter A | title = No evidence for the expression of the progesterone receptor on peripheral blood lymphocytes during pregnancy | journal = Human Reproduction | volume = 9 | issue = 8 | pages = 1546–9 | date = August 1994 | pmid = 7989520 | doi = 10.1093/oxfordjournals.humrep.a138746 }}
* {{cite journal | vauthors = Kalkhoven E, Wissink S, van der Saag PT, van der Burg B | title = Negative interaction between the RelA(p65) subunit of NF-kappaB and the progesterone receptor | journal = The Journal of Biological Chemistry | volume = 271 | issue = 11 | pages = 6217–24 | date = March 1996 | pmid = 8626413 | doi = 10.1074/jbc.271.11.6217 }}
* {{cite journal | vauthors = Wang JD, Zhu JB, Fu Y, Shi WL, Qiao GM, Wang YQ, Chen J, Zhu PD | title = Progesterone receptor immunoreactivity at the maternofetal interface of first trimester pregnancy: a study of the trophoblast population | journal = Human Reproduction | volume = 11 | issue = 2 | pages = 413–9 | date = February 1996 | pmid = 8671234 | doi = 10.1093/humrep/11.2.413 }}
* {{cite journal | vauthors = Thénot S, Henriquet C, Rochefort H, Cavaillès V | title = Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1 | journal = The Journal of Biological Chemistry | volume = 272 | issue = 18 | pages = 12062–8 | date = May 1997 | pmid = 9115274 | doi = 10.1074/jbc.272.18.12062 }}
* {{cite journal | vauthors = Jenster G, Spencer TE, Burcin MM, Tsai SY, Tsai MJ, O'Malley BW | title = Steroid receptor induction of gene transcription: a two-step model | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 15 | pages = 7879–84 | date = July 1997 | pmid = 9223281 | pmc = 21523 | doi = 10.1073/pnas.94.15.7879 }}
* {{cite journal | vauthors = Shanker YG, Sharma SC, Rao AJ | title = Expression of progesterone receptor mRNA in the first trimester human placenta | journal = Biochemistry and Molecular Biology International | volume = 42 | issue = 6 | pages = 1235–40 | date = September 1997 | pmid = 9305541 | doi = 10.1080/15216549700203701}}
* {{cite journal | vauthors = Richer JK, Lange CA, Wierman AM, Brooks KM, Tung L, Takimoto GS, Horwitz KB | title = Progesterone receptor variants found in breast cells repress transcription by wild-type receptors | journal = Breast Cancer Research and Treatment | volume = 48 | issue = 3 | pages = 231–41 | date = April 1998 | pmid = 9598870 | doi = 10.1023/A:1005941117247 }}
* {{cite journal | vauthors = Williams SP, Sigler PB | title = Atomic structure of progesterone complexed with its receptor | journal = Nature | volume = 393 | issue = 6683 | pages = 392–6 | date = May 1998 | pmid = 9620806 | doi = 10.1038/30775 }}
* {{cite journal | vauthors = Boonyaratanakornkit V, Melvin V, Prendergast P, Altmann M, Ronfani L, Bianchi ME, Taraseviciene L, Nordeen SK, Allegretto EA, Edwards DP | title = 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 | journal = Molecular and Cellular Biology | volume = 18 | issue = 8 | pages = 4471–87 | date = August 1998 | pmid = 9671457 | pmc = 109033 | doi = 10.1128/mcb.18.8.4471}}
* {{cite journal | vauthors = Nawaz Z, Lonard DM, Smith CL, Lev-Lehman E, Tsai SY, Tsai MJ, O'Malley BW | title = The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily | journal = Molecular and Cellular Biology | volume = 19 | issue = 2 | pages = 1182–9 | date = February 1999 | pmid = 9891052 | pmc = 116047 | doi = 10.1128/mcb.19.2.1182}}
{{refend}}

== External links ==
* {{MeshName|Progesterone+Receptors}}

{{PDB Gallery|geneid=5241}}
{{Transcription factors|g2}}
{{Progestogenics}}
{{InterPro content|IPR000342}}

[[Category:Intracellular receptors]]
[[Category:Progestogens]]
[[Category:Transcription factors]]

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Progesterone receptor