|March 26, 2016|
Estrogen receptor refers to a group of receptor s that are activated by the hormone 17??-estradiol (estrogen). Two types of estrogen receptor exist: ER , which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 (GPER), which is a G protein-coupled receptor. This article refers to the nuclear hormone receptor ER.
The main function of the estrogen receptor is as a DNA-binding transcription factor that regulates gene expression. However, the estrogen receptor has additional functions independent of DNA binding.
There are two different forms of the estrogen receptor, usually referred to as ?? and ?? , each encoded by a separate gene ( and , respectively). Hormone-activated estrogen receptors form dimer s, and, since the two forms are coexpressed in many cell types, the receptors may form ER?? (????) or ER?? (????) homodimers or ER???? (????) heterodimers.
Estrogen receptor alpha and beta show significant overall sequence homology, and both are composed of five domains (listed from the N- to C-terminus; amino acid sequence numbers refer to human ER):(A-F domain)
The N-terminal A/B domain is able to transactivate gene transcription in the absence of bound ligand (e.g., the estrogen hormone). While this region is able to activate gene transcription without ligand, this activation is weak and more selective compared to the activation provided by the E domain. The C domain, also known as the DNA-binding domain, binds to estrogen response elements in DNA. The D domain is a hinge region that connects the C and E domains. The E domain contains the ligand binding cavity as well as binding sites for coactivator and corepressor proteins. The E-domain in the presence of bound ligand is able to activate gene transcription. The C-terminal F domain function is not entirely clear and is variable in length.
Due to alternative RNA splicing, several ER isoforms are known to exist. At least three ERalpha and five ERbeta isoforms have been identified. The ERbeta isoforms receptor subtypes can transactivate transcription only when a heterodimer with the functional ER??1 receptor of 59 kDa is formed. The ER??3 receptor was detected at high levels in the testis. The two other ERalpha isoforms are 36 and 46kDa.
Only in fish, but not in humans, an ERgamma receptor has been described.
The two forms of the estrogen receptor are encoded by different genes, and on the sixth and fourteenth chromosome (6q25.1 and 14q23.2), respectively.
Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns:
The ERs are regarded to be cytoplasmic receptors in their unliganded state, but visualization research has shown that a fraction of the ERs resides in the nucleus.
The "ER??" primary transcript gives rise to several alternatively spliced variants of unknown function .
The ER's helix 12 domain plays a crucial role in determining interactions with coactivators and corepressors and, therefore, the respective agonist or antagonist effect of the ligand.
Different ligands may differ in their affinity for alpha and beta isoforms of the estrogen receptor:
Subtype selective estrogen receptor modulators preferentially bind to either the ??- or the ??-subtype of the receptor. In addition, the different estrogen receptor combinations may respond differently to various ligands, which may translate into tissue selective agonistic and antagonistic effects.
The concept of selective estrogen receptor modulators is based on the ability to promote ER interactions with different proteins such as transcriptional coactivator or corepressor s. Furthermore, the ratio of coactivator to corepressor protein varies in different tissues. but an ER agonist in bone (thereby preventing osteoporosis) and a partial agonist in the endometrium (increasing the risk of uterine cancer) .
Since estrogen is a steroidal hormone, it can pass through the phospholipid membranes of the cell, and receptors therefore do not need to be membrane-bound in order to bind with estrogen.
In the absence of hormone, estrogen receptors are largely located in the cytosol. Hormone binding to the receptor triggers a number of events starting with migration of the receptor from the cytosol into the nucleus, dimerization of the receptor, and subsequent binding of the receptor dimer to specific sequences of DNA known as hormone response elements. The DNA/receptor complex then recruits other proteins that are responsible for the transcription of downstream DNA into mRNA and finally protein that results in a change in cell function. Estrogen receptors also occur within the cell nucleus, and both estrogen receptor subtypes have a DNA-binding domain and can function as transcription factors to regulate the production of proteins.
The receptor also interacts with activator protein 1 and Sp-1 to promote transcription, via several coactivators such as PELP-1.
Some estrogen receptors associate with the cell surface membrane and can be rapidly activated by exposure of cells to estrogen.
In addition, some ER may associate with cell membranes by attachment to caveolin-1 and form complexes with G proteins, striatin , receptor tyrosine kinases (e.g., EGFR and IGF-1), and non-receptor tyrosine kinases (e.g., Src ). Through striatin, some of this membrane bound ER may lead to increased levels of Ca2+ and nitric oxide (NO). Glycogen synthase kinase-3 (GSK)-3?? inhibits transcription by nuclear ER by inhibiting phosphorylation of serine 118 of nuclear ER??. Phosphorylation of GSK-3?? removes its inhibitory effect, and this can be achieved by the PI3K/AKT pathway and the MAPK/ERK pathway, via rsk .
17??-Estradiol has been shown to activate the G protein-coupled receptor GPR30.
Studies in female mice have shown that estrogen receptor-alpha declines in the pre-optic hypothalamus as they grow old. Female mice that were given a calorically restricted diet during the majority of their lives maintained higher levels of ER?? in the pre-optic hypothalamus than their non-calorically restricted counterparts.
Estrogen receptors are over-expressed in around 70% of breast cancer cases, referred to as "ER-positive". Two hypotheses have been proposed to explain why this causes tumorigenesis, and the available evidence suggests that both mechanisms contribute:
The result of both processes is disruption of cell cycle, apoptosis and DNA repair, and, therefore, tumour formation. ER?? is certainly associated with more differentiated tumours, while evidence that ER?? is involved is controversial. Different versions of the ESR1 gene have been identified (with single-nucleotide polymorphisms) and are associated with different risks of developing breast cancer.
Endocrine therapy for breast cancer involves selective estrogen receptor modulators (SERMS), which behave as ER antagonists in breast tissue or aromatase inhibitors. ER status is used to determine sensitivity of breast cancer lesions to tamoxifen and aromatase inhibitors. Another SERM, raloxifene, has been used as a preventative chemotherapy for women judged to have a high risk of developing breast cancer. Another chemotherapeutic anti-estrogen, ICI 182,780 (Faslodex), which acts as a complete antagonist, also promotes degradation of the estrogen receptor.
Estrogen and the ERs have also been implicated in breast cancer, ovarian cancer, colon cancer, prostate cancer, and endometrial cancer. Advanced colon cancer is associated with a loss of ER??, the predominant ER in colon tissue, and colon cancer is treated with ER??-specific agonists.
A dramatic demonstration of the importance of estrogens in the regulation of fat deposition comes from transgenic mice that were genetically engineered to lack a functional aromatase gene. These mice have very low levels of estrogen and are obese.
Estrogen receptors were first identified by Elwood V. Jensen at the University of Chicago in the 1950s,
GNU Free Documentation License. It uses material from the Wikipedia article "estrogen receptor".
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