Progesterone receptor

Progesterone receptor
PDB rendering based on 1a28.
Available structures PDB 1A28, 1E3K, 1SQN, 1SR7, 1ZUC, 2C7A, 2OVH, 2OVM, 2W8Y, 3D90, 3G8N, 3G8O, 3HQ5, 3KBA
Identifiers
Symbols	PGR; NR3C3; PR
External IDs	OMIM: 607311 MGI: 97567 HomoloGene: 713 IUPHAR: GeneCards: PGR Gene
Gene Ontology Molecular function • DNA binding • sequence-specific DNA binding transcription factor activity • steroid hormone receptor activity • receptor binding • steroid binding • protein binding • zinc ion binding • enzyme binding • hormone binding • sequence-specific DNA binding • metal ion binding Cellular component • nucleus • nucleoplasm • nucleolus • cytoplasm • neuron projection • intracellular membrane-bounded organelle Biological process • ovulation from ovarian follicle • epithelial cell maturation • signal transduction • cell-cell signaling • gene expression • mammary gland development • regulation of transcription from RNA polymerase II promoter by nuclear hormone receptor • steroid hormone mediated signaling pathway • negative regulation of transcription, DNA-dependent • positive regulation of transcription, DNA-dependent • regulation of epithelial cell proliferation • progesterone receptor signaling pathway • tertiary branching involved in mammary gland duct morphogenesis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5241	18667
Ensembl	ENSG00000082175	ENSMUSG00000031870
UniProt	P06401	Q8BW69
RefSeq (mRNA)	NM_000926.4	NM_008829.2
RefSeq (protein)	NP_000917.3	NP_032855.2
Location (UCSC)	Chr 11: 100.9 – 101 Mb	Chr 9: 8.9 – 8.97 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. In humans, PR is encoded by a single PGR gene residing on chromosome 11q22,^[1][2] it has two main forms, A and B, that differ in their molecular weight.^[3][4][5]

Background

Progesterone receptor, N-terminal
Identifiers
Symbol	Progest_rcpt_N
Pfam	PF02161
InterPro	IPR000128
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

Steroid or nuclear hormone receptors (NRs) constitute an important superfamily of transcription regulators that are involved in widely diverse physiological functions, including control of embryonic development, cell differentiation and homeostasis. Members of the superfamily include the steroid hormone receptors and receptors for thyroid hormone, retinoids, 1,25-dihydroxy-vitamin D3 and a variety of other ligands. The proteins function as dimeric molecules in nuclei to regulate the transcription of target genes in a ligand-responsive manner.^[6][7] In addition to C-terminal ligand-binding domains, these nuclear receptors contain a highly-conserved, N-terminal zinc-finger that mediates specific binding to target DNA sequences, termed ligand-responsive elements. In the absence of ligand, steroid hormone receptors are thought to be weakly associated with nuclear components; hormone binding greatly increases receptor affinity.

NRs are extremely important in medical research, a large number of them being implicated in diseases such as cancer, diabetes, hormone resistance syndromes, etc. While several NRs act as ligand-inducible transcription factors, many do not yet have a defined ligand and are accordingly termed "orphan" receptors. During the last decade, more than 300 NRs have been described, many of which are orphans, which cannot easily be named due to current nomenclature has recently been introduced in an attempt to rationalise the increasingly complex set of names used to describe superfamily members.

Structure

In common with other steroid receptors, the progesterone receptor has a N-terminal regulatory domain, a DNA binding domain, a hinge section, and a 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

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.^[8] 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 .^[9] 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.^[10]

Several studies have now shown no association between progesterone receptor gene +331G/A polymorphisms and breast or endometrial cancers.^[11][12] 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.

Antagonists

Progesterone receptor antagonists work as antiprogestins. The main example is mifepristone. Selective progesterone receptor modulators may also have more or less antagonist activity.

Interactions

Progesterone receptor has been shown to interact with:

• KLF9,^[13]
• Nuclear receptor co-repressor 2,^[14] and
• UBE3A.^[15]

See also

• Selective progesterone receptor modulator

References

1. ^ Misrahi M, Atger M, d'Auriol L, Loosfelt H, Meriel C, Fridlansky F, Guiochon-Mantel A, Galibert F, Milgrom E (March 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. 
2. ^ Law ML, Kao FT, Wei Q, Hartz JA, Greene GL, Zarucki-Schulz T, Conneely OM, Jones C, Puck TT, O'Malley BW (May 1987). "The progesterone receptor gene maps to human chromosome band 11q13, the site of the mammary oncogene int-2". Proc. Natl. Acad. Sci. U.S.A. 84 (9): 2877–81. doi:10.1073/pnas.84.9.2877. PMC 304763. PMID 3472240. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=304763. 
3. ^ 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. 
4. ^ Kase, Nathan G.; Speroff, Leon; Glass, Robert L. (1999). Clinical gynecologic endocrinology and infertility. Hagerstown, MD: Lippincott Williams & Wilkins. ISBN 0-683-30379-1. 
5. ^ Fritz, Marc A.; Speroff, Leon (2005). Clinical gynecologic endocrinology and infertility. Hagerstown, MD: Lippincott Williams & Wilkins. ISBN 0-7817-4795-3. 
6. ^ Nishihara T, Kitaura M, Imagawa M, Nishikawa J (1995). "Vitamin D receptor contains multiple dimerization interfaces that are functionally different". Nucleic Acids Res. 23 (4): 606–611. doi:10.1093/nar/23.4.606. PMC 306727. PMID 7899080. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=306727. 
7. ^ Schmitt J, De Vos P, Verhoeven G, Stunnenberg HG (1994). "Human androgen receptor expressed in HeLa cells activates transcription in vitro". Nucleic Acids Res. 22 (7): 1161–1166. doi:10.1093/nar/22.7.1161. PMC 523637. PMID 8165128. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=523637. 
8. ^ 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. PMC 551856. PMID 2328727. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=551856. 
9. ^ 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. PMC 1380205. PMID 15718480. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1380205. 
10. ^ 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. PMC 129433. PMID 12218173. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=129433. 
11. ^ 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. 
12. ^ 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. 
13. ^ Zhang XL, Zhang D, Michel FJ, Blum JL, Simmen FA, Simmen RC (June 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. 278 (24): 21474–82. doi:10.1074/jbc.M212098200. PMID 12672823. 
14. ^ Giangrande PH, Kimbrel EA, Edwards DP, McDonnell DP (May 2000). "The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding". Mol. Cell. Biol. 20 (9): 3102–15. doi:10.1128/MCB.20.9.3102-3115.2000. PMC 85605. PMID 10757795. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=85605. 
15. ^ Nawaz Z, Lonard DM, Smith CL, Lev-Lehman E, Tsai SY, Tsai MJ, O'Malley BW (February 1999). "The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily". Mol. Cell. Biol. 19 (2): 1182–9. PMC 116047. PMID 9891052. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=116047. 

Further reading

• Butnor KJ, Burchette JL, Robboy SJ (2002). "Progesterone receptor activity in leiomyomatosis peritonealis disseminata". Int. J. Gynecol. Pathol. 18 (3): 259–64. doi:10.1097/00004347-199907000-00012. 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. PMC 48722. PMID 1557371. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=48722. 
• 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. PMC 551856. PMID 2328727. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=551856. 
• 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. 
• 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. PMC 1427833. PMID 6849751. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1427833. 
• 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. PMC 21523. PMID 9223281. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=21523. 
• 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. PMC 109033. PMID 9671457. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=109033. 
• 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. PMC 116047. PMID 9891052. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=116047. 

External links

• MeSH Progesterone+Receptors

This article includes text from the public domain Pfam and InterPro IPR000342