Progesterone receptor
Encyclopedia
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, it has two main forms, A and B, that differ in their molecular weight.
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.
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 is of significance to cancer.
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 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.
s. The main example is mifepristone
. Selective progesterone receptor modulator
s may also have more or less antagonist activity.
with:
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
subfamily 3, group C, member 3), is an intracellular steroid receptor that specifically binds progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
. In humans, PR is encoded by a single PGR gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
residing on chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
11q22, it has two main forms, A and B, that differ in their molecular weight.
Background
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. 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
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, 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. 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 . 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 is of significance to cancer.
Function
EstrogenEstrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
is necessary to induce the progesterone receptors. When no binding hormone is present the carboxyl terminal inhibits transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
. 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 dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
ization follows and the complex enters the nucleus and binds to DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
. There transcription takes place, resulting in formation of messenger RNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
that is translated by ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
s to produce specific proteins.
Antagonists
Progesterone receptor antagonists work as antiprogestinAntiprogestin
An antiprogestin is a substance that prevents cells from making or using progesterone . Antiprogestins may stop some cancer cells from growing and they are being studied in the treatment of breast cancer...
s. The main example is mifepristone
Mifepristone
Mifepristone is a synthetic steroid compound used as a pharmaceutical. It is a progesterone receptor antagonist used as an abortifacient in the first months of pregnancy, and in smaller doses as an emergency contraceptive. During early trials, it was known as RU-38486 or simply RU-486, its...
. Selective progesterone receptor modulator
Selective progesterone receptor modulator
A selective progesterone receptor modulator is an agent that acts on the progesterone receptor. A characteristic that distinguishes such substances from receptor full agonists and full antagonists is that their action differs in different tissues...
s may also have more or less antagonist activity.
Interactions
Progesterone receptor has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- KLF9KLF9Krueppel-like factor 9 is a protein that in humans is encoded by the KLF9 gene.-Interactions:KLF9 has been shown to interact with Progesterone receptor....
, - Nuclear receptor co-repressor 2Nuclear receptor co-repressor 2The nuclear receptor co-repressor 2 is a transcriptional coregulatory protein that contains several nuclear receptor-interacting domains. In addition, NCOR2 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR2 assists nuclear receptors in the down regulation of target...
, and - UBE3AUBE3AUbiquitin-protein ligase E3A also known as E6AP ubiquitin-protein ligase is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells...
.