Biology:Progesterone receptor

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

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 TAF3, 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 articles: Biology:Progesterone receptor A, Progesterone receptor B, and Progesterone receptor C

The single-copy human (hPR) gene uses separate promoters and translational start sites to produce three isoforms, PR-A, -B, and -C. PR-A and -B are identical except for an additional 165 amino acids present only in the N terminus of PR-B. PR-C is even smaller, starting at the 595th amino acid of PR-B. Although the three isoforms share many important structural domains, they are functionally distinct.

PR-A and PR-B are disticnt transcription factors, which mediate their own response genes and physiological effects with little overlap.

PR-C being the smallest, does not have the important AF1, AF3, or DNA-binding domains. Thus, PR-C is not a transcription factor. However, PR-C can dimerize, participate in nuclear translocation, and modulate the actions of PR-A and PR-B.

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 . 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.

Several studies have now shown no association between progesterone receptor gene +331G/A polymorphisms and breast or endometrial cancers. 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. A study of 21 non-European populations identified two markers within the PROGINS haplotype of the PR gene as positively correlated with ovarian and breast cancer.

Animal studies

Development

Knockout mice of the PR have been found to have severely impaired lobuloalveolar development of the mammary glands as well as delayed but otherwise normal mammary ductal development at puberty.

Behavior

During rodent perinatal life, progesterone receptor (PR) is known to be transiently expressed in both the ventral tegmental area (VTA) and the medial prefrontal cortex (mPFC) of the mesocortical dopaminergic pathway. PR activity during this time period impacts the development of dopaminergic innervation of the mPFC from the VTA. If PR activity is altered, a change in dopaminergic innervation of the mPFC is seen and tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis, in the VTA will also be impacted. TH expression in this area is an indicator of dopaminergic activity, which is believed to be involved in normal and critical development of complex cognitive behaviors that are mediated by the mesocortical dopaminergic pathway, such as working memory, attention, behavioral inhibition, and cognitive flexibility.

Research has shown that when a PR antagonist, such as RU486 (also known as mifepristone), is administered to rats during the neonatal period, decreased tyrosine hydroxylase immunoreactive (TH-ir) cells density, a strong co-expresser with PR-immunoreactivity (PR-ir), is seen in the mPFC of juvenile rodents. Later on, in adulthood, decreased levels of TH-ir in the VTA are also shown. This alteration in TH-ir fiber expression, an indicator of altered dopaminergic activity resulting from neonatal PR antagonist administration, has been shown to impair later performance on tasks that measure behavioral inhibition and impulsivity, as well as cognitive flexibility in adulthood. Similar cognitive flexibility impairments were also seen in PR knockout mice as a result of reduced dopaminergic activity in the VTA.

Conversely, when a PR agonist, such as 17α-hydroxyprogesterone caproate, is administered to rodents during perinatal life, as the mesocortical dopaminergic pathway is developing, dopaminergic innervation of the mPFC increases. As a result, TH-ir fiber density also increases. Interestingly, this increase in TH-ir fibers and dopaminergic activity is also linked to impaired cognitive flexibility with increased perseveration later on in life.

In combination, these findings suggest that PR expression during early development impact later cognitive functioning in rodents. Furthermore, it appears as though abnormal levels of PR activity during this critical period of mesocortical dopaminergic pathway development may have profound effects on specific behavioral neural circuits involved in the formation of later complex cognitive behavior.

Ligands

Agonists

• Endogenous progestogens (e.g., progesterone)
• Synthetic progestogens (e.g., norethisterone, levonorgestrel, medroxyprogesterone acetate, megestrol acetate, dydrogesterone, drospirenone)
• Certain corticosteroids (Mometasone)

Mixed

• Selective progesterone receptor modulators (e.g., ulipristal acetate, telapristone acetate, vilaprisan, asoprisnil, asoprisnil ecamate)

Antagonists

• Antiprogestogens (e.g., mifepristone, aglepristone, onapristone, lonaprisan, lilopristone, toripristone)

Interactions

Progesterone receptor has been shown to interact with many other proteins since it is a transcription factor with many cofactors. A small selection of these includes:

• KLF9,
• Nuclear receptor co-repressor 2, and
• UBE3A.
• Estrogen receptor

See also

• Membrane progesterone receptor
• Selective progesterone receptor modulator
• Phytoprogestogen

Further reading

• "Progesterone receptor activity in leiomyomatosis peritonealis disseminata". International Journal of Gynecological Pathology 18 (3): 259–64. July 1999. doi:10.1097/00004347-199907000-00012. PMID 12090595. 
• "Progesterone receptor transcription and non-transcription signaling mechanisms". Steroids 68 (10–13): 761–70. November 2003. doi:10.1016/S0039-128X(03)00129-6. PMID 14667966. 
• "Progesterone-dependent regulation of female reproductive activity by two distinct progesterone receptor isoforms". Steroids 68 (10–13): 771–8. November 2003. doi:10.1016/S0039-128X(03)00126-0. PMID 14667967. 
• "Ligand and DNA-dependent phosphorylation of human progesterone receptor in vitro". Proceedings of the National Academy of Sciences of the United States of America 89 (7): 2664–8. April 1992. doi:10.1073/pnas.89.7.2664. PMID 1557371. Bibcode: 1992PNAS...89.2664B. 
• "Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B". The EMBO Journal 9 (5): 1603–14. May 1990. doi:10.1002/j.1460-2075.1990.tb08280.x. PMID 2328727. 
• "Mechanisms of nuclear localization of the progesterone receptor: evidence for interaction between monomers". Cell 57 (7): 1147–54. June 1989. doi:10.1016/0092-8674(89)90052-4. PMID 2736623. 
• "The interaction of canrenone with oestrogen and progesterone receptors in human uterine cytosol". British Journal of Clinical Pharmacology 15 (1): 95–101. January 1983. doi:10.1111/j.1365-2125.1983.tb01470.x. PMID 6849751. 
• "Sequence and characterization of a coactivator for the steroid hormone receptor superfamily". Science 270 (5240): 1354–7. November 1995. doi:10.1126/science.270.5240.1354. PMID 7481822. Bibcode: 1995Sci...270.1354O. 
• "Identification of phosphorylation sites unique to the B form of human progesterone receptor. In vitro phosphorylation by casein kinase II". The Journal of Biological Chemistry 269 (49): 31034–40. December 1994. doi:10.1016/S0021-9258(18)47386-3. PMID 7983041. 
• "No evidence for the expression of the progesterone receptor on peripheral blood lymphocytes during pregnancy". Human Reproduction 9 (8): 1546–9. August 1994. doi:10.1093/oxfordjournals.humrep.a138746. PMID 7989520. 
• "Negative interaction between the RelA(p65) subunit of NF-kappaB and the progesterone receptor". The Journal of Biological Chemistry 271 (11): 6217–24. March 1996. doi:10.1074/jbc.271.11.6217. PMID 8626413. 
• "Progesterone receptor immunoreactivity at the maternofetal interface of first trimester pregnancy: a study of the trophoblast population". Human Reproduction 11 (2): 413–9. February 1996. doi:10.1093/humrep/11.2.413. PMID 8671234. 
• "Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1". The Journal of Biological Chemistry 272 (18): 12062–8. May 1997. doi:10.1074/jbc.272.18.12062. PMID 9115274. 
• "Steroid receptor induction of gene transcription: a two-step model". Proceedings of the National Academy of Sciences of the United States of America 94 (15): 7879–84. July 1997. doi:10.1073/pnas.94.15.7879. PMID 9223281. Bibcode: 1997PNAS...94.7879J. 
• "Expression of progesterone receptor mRNA in the first trimester human placenta". Biochemistry and Molecular Biology International 42 (6): 1235–40. September 1997. doi:10.1080/15216549700203701. PMID 9305541. 
• "Progesterone receptor variants found in breast cells repress transcription by wild-type receptors". Breast Cancer Research and Treatment 48 (3): 231–41. April 1998. doi:10.1023/A:1005941117247. PMID 9598870. 
• "Atomic structure of progesterone complexed with its receptor". Nature 393 (6683): 392–6. May 1998. doi:10.1038/30775. PMID 9620806. Bibcode: 1998Natur.393..392W. 
• "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". Molecular and Cellular Biology 18 (8): 4471–87. August 1998. doi:10.1128/mcb.18.8.4471. PMID 9671457. 
• "The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily". Molecular and Cellular Biology 19 (2): 1182–9. February 1999. doi:10.1128/mcb.19.2.1182. PMID 9891052. 

External links

• Progesterone+Receptors at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the public domain Pfam and InterPro: IPR000342