25-01-2014, 07:59 PM
To illustrate Estrogen Receptors!
Estrogen receptors
Estrogen receptors are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol).[1] Two classes of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and GPR30, which is a member of the rhodopsin-like family of G protein-coupled receptors. This article refers to the former (ER).
Once activated by estrogen, the ER is able to translocate into the nucleus and bind to DNA to regulate the activity of different genes (i.e. it is a DNA-binding transcription factor). However, it also has additional functions independent of DNA binding.[2]
Proteomics
There are two different forms of the estrogen receptor, usually referred to as α and β, each encoded by a separate gene (ESR1 and ESR2, respectively). Hormone-activated estrogen receptors form dimers, and, since the two forms are coexpressed in many cell types, the receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers.[3] 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)
Distribution
Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns:[7]
The ERα is found in endometrium, breast cancer cells, ovarian stromal cells, and the hypothalamus.[8] In males, ERα protein is found in the epithelium of the efferent ducts.[9]
The expression of the ERβ protein has been documented in ovarian granulosa cells, kidney, brain, bone, heart,[10] lungs, intestinal mucosa, prostate, and endothelial cells.
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.[11] The "ERα" primary transcript gives rise to several alternatively spliced variants of unknown function.[12]
Different ligands may differ in their affinity for alpha and beta isoforms of the estrogen receptor:
17-beta-estradiol binds equally well to both receptors
estrone, and raloxifene bind preferentially to the alpha receptor
estriol, and genistein to the beta receptor
Cancer
Estrogen receptors are over-expressed in around 70% of breast cancer cases, referred to as "ER-positive", and can be demonstrated in such tissues using immunohistochemistry. Two hypotheses have been proposed to explain why this causes tumorigenesis, and the available evidence suggests that both mechanisms contribute:
First, binding of estrogen to the ER stimulates proliferation of mammary cells, with the resulting increase in cell division and DNA replication, leading to mutations.
Second, estrogen metabolism produces genotoxic waste.
The result of both processes is disruption of cell cycle, apoptosis and DNA repair, and, therefore, tumour formation. ERα is certainly associated with more differentiated tumours, while evidence that ERβ 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.[18]
Phytoestrogens such as quercetin can modulate estrogen receptor’s activities in such a way that it may prevent cancers including breasts, prostate, and colon all by promoting apoptosis.[29] Quercetin selectively binds to the estrogen receptor beta (ERβ).[30] This was tested in HeLa cells which were treated with a pure estrogen receptor antagonist which blocked both estradiol and quercetin from inducing the caspase-3 activation.[29] ERβ is expressed in the human colon and activates a specific signal transduction pathway that controls apoptosis in the colon and works by being activated by estradiol and more recently found to possibly be activated by quercetin.[29] Quercetin activates the ERβ along with the apoptotic cascade when caspase-3 is present by the phosphorylation of p38 kinase. In colon cancers and tumors ERβ and its pathway have been proven to be significantly decreased thus allowing the tumors to thrive.[31]
http://wikipedia.org/wiki/Estrogen_receptor