Gene Expression

By: Pharma Tips | Views: 5282 | Date: 29-Jun-2010

Nuclear receptors are a superfamily of ligand activated transcription factors that modulate specific gene expression.

Gene Expression

Nuclear receptors are a superfamily of ligand activated transcription factors that modulate specific gene expression.
Currently there are 100 nuclear receptor are identified[1].

In the field of molecular biology, nuclear receptors are a class of proteins found within other molecules. In response, these receptors work in concert with other proteins to regulate the expression of specific genes thereby controlling the development, homeostasis, and metabolism of the organism.
Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes, hence these receptors are classified as transcription factors. The regulation of gene expression by nuclear receptors only happens when a ligand—a molecule which affects the receptor's behavior is present. More specifically, ligand binding to a nuclear receptor results in a conformational change in the receptor which in turn activates the receptor resulting in up-regulation of gene expression.
A unique property of nuclear receptors which differentiate them from other classes of receptors is their ability to directly interact with and control the expression of genomic DNA. Consequently nuclear receptors play key roles in both the embryonic development and adult homeostasis of organisms [2, 3, 4].

Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones, vitamins A and D, and xenobiotic endocrine disruptors. Because the expression of a large number of genes is regulated by nuclear receptors, ligands that activate these receptors can have profound effects on the organism. Many of these regulated genes are associated with various diseases which explains why the molecular targets of approximately 13% of FDA approved drugs are nuclear receptors
A number of nuclear receptors, referred to as orphan receptors, have no known endogenous ligands. Some of these receptors such as FXR, LXR, and PPAR bind a number of metabolic intermediates such as fatty acids, bile acids and/or sterols with relatively low affinity. These receptors hence may function as metabolic sensors. Other nuclear receptors, such as CAR and PXR appear to function as xenobiotic sensors up-regulating the expression of cytochrome P450 enzymes that metabolize these xenobiotics[5].
Structural Organization ofNuclearReceptors
Top – Schematic 1D amino acid sequence of a nuclear receptor.
Bottom – 3D structures of the DBD (bound to DNA) and LBD (bound to hormone) regions of the nuclear receptor. The structures shown are of the estrogen receptor. Experimental structures of N-terminal domain (A/B), hinge region (D), and C-terminal domain (E) have not been determined therefore are represented by red, purple, and orange dashed lines respectively.
Nuclear receptors are modular in structure and contain the following domains:
A-B) N-terminal regulatory domain: Contains the activation function 1 (AF-1) whose action is independent of the presence of ligand. The transcriptional activation of AF-1 is normally very weak, but it does synergize with AF-2 (see below) to produce a more robust upregulation of gene expression. The A-B domain is highly variable in sequence between various nuclear receptors.
C) DNA-binding domain (DBD): Highly conserved domain containing two zinc fingers which binds to specific sequences of DNA called hormone response elements (HRE).
D) Hinge region: Thought to be a flexible domain which connects the DBD with the LBD. Influences intracellular trafficking and subcellular distribution.
E) Ligand binding domain (LBD): Moderately conserved in sequence and highly conserved in structure between the various nuclear receptors.
in which three anti parallel alpha helices (the "sandwich filling") are The structure of the LBD is referred to as an alpha helical sandwich fold (SCOP flanked by two alpha helices on one side and three on the other (the "bread"). The ligand binding cavity is within the interior of the LBD and just below three anti parallel alpha helical sandwich "filling". Along with the DBD, the LBD contributes to the dimerization interface of the receptor and in addition, binds coactivator and corepressor proteins. Contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand.
F) C-terminal domain: Variable in sequence between various nuclear receptors [7-12]. 


Mechanism nuclear receptor action: This figure depicts the mechanism of a class II nuclear receptor (NR) which, regardless of ligand binding status is located in the nucleus bound to DNA. For the purpose of illustration, the nuclear receptor shown here is the thyroid hormone receptor (TR) heterodimerized to the RXR. In the absence of ligand, the TR is bound to corepressor protein. Ligand binding to TR causes a dissociation of corepressor and recruitment of coactivator protein which in turn recruit additional proteins such as RNA polymerase that are responsible for translation of downstream DNA into RNA and eventually protein which results in a change in cell function.
Nuclear receptors (NRs) may be classified into two broad classes according to their mechanism of action and subcellular distribution in the absence of ligand.
Small lipophilic substances such as natural hormones diffuse past the cell membrane and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell. This causes a change in the conformation of the receptor which depending on the mechanistic class (type I or II), triggers a number of down stream events that eventually results in up or down regulation of gene expression.
Accordingly, nuclear receptors may be subdivided into the following four mechanistic classes.
Type I
Ligand binding to type I nuclear receptors in the cytosol (includes members of the NR subfamily 3) results in the dissociation of heat shock proteins, homo-dimerization, translocation (i.e., active transport) from the cytoplasm into the cell nucleus, and binding to specific sequences of DNA known as hormone response elements (HRE's). Type I nuclear receptors bind to HREs consisting of two half sites separated by a variable length of DNA and the second half site has a sequence inverted from the first (inverted repeat).
The nuclear receptor/DNA complex then recruits other proteins which transcribe DNA downstream from the HRE into messenger RNA and eventually protein which causes a change in cell function.
 Type II
Type II receptors (principally NR subfamily 1) in contrast are retained in the nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR) to DNA. In the absence of ligand, type II nuclear receptors are often complexed with corepressor proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator proteins. Additional proteins including RNA polymerase are then recruited to the NR/DNA complexes which transcribe DNA into messenger RNA.
 Type III
Type III nuclear receptors (principally NR subfamily 2) are similar to type I receptors in that both classes bind to DNA as homodimers. However, type III nuclear receptors, in contrast to type I, bind to direct repeat instead of inverted repeat HREs.
 Type IV
Type IV nuclear receptors bind either as monomers or dimers, but only a single DNA binding domain of the receptor binds to a single half site HRE. Examples of type IV receptors are found in most of the NR subfamilies [13-17]

Nuclear receptors bound to hormone response elements recruit a significant number of other proteins (referred to as transcription coregulators) which facilitate or inhibit the transcription of the associated target gene into mRNA.The function of these coregulators are varied and include chromatin remodeling (making the target gene either more or less accessible to transcription) or a bridging function to stabilize the binding of other coregulatory proteins.
Binding of agonist ligands (see section below) to nuclear receptors induces a conformation of the receptor that preferentially binds coactivator proteins. These proteins often have an intrinsic histone acetyltransferase (HAT) activity which weakens the association of histones to DNA, and therefore promotes gene transcription.
Binding of antagonist ligands to nuclear receptors in contrast induces a conformation of the receptor that preferentially binds corepressor proteins. These proteins in turn recruit histone deacetylases (HDACs) which strengthens the association of histones to DNA, and therefore represses gene transcription [18-20].

Depending on the receptor involved, the chemical structure of the ligand and the tissue that is being affected, nuclear receptor ligands may display dramatically diverse effects ranging in a spectrum from agonism to antagonism to inverse agonism.
The activity of endogenous ligands (such as the hormones estradiol and testosterone) when bound to their cognate nuclear receptors is normally to upregulate gene expression. This stimulation of gene expression by the ligand is referred to as an agonist response. The agonistic effects of endogenous hormones can also be mimicked by certain synthetic ligands, for example, the glucocorticoid receptor antiiflammatory drug dexamethasone. Agonist ligands work by inducing a conformation of the receptor which favors coactivator binding (see upper half of the figure to the right).
Other synthetic nuclear receptor ligands have no apparent effect on gene transcription in the absence of endogenous ligand. However they block the effect of agonist through competitive binding to the same binding site in the nuclear receptor. These ligands are referred to as antagonists. An example of antagonistic nuclear receptor drug is mifepristone which binds to the glucocorticoid and progesterone receptors and therefore blocks the activity of the endogenous hormones cortisol and progesterone respectively. Antagonist ligands work by inducing a conformation of the receptor which prevents coactivator and promotes corepressor binding 
Inverse agonists
Finally, some nuclear receptors promote a low level of gene transcription in the absence of agonists (also referred to as basal or constitutive activity). Synthetic ligands which reduce this basal level of activity in nuclear receptors are known as inverse agonists [21].

A number of drugs that work through nuclear receptors display an agonist response in some tissues and an antagonistic response in other tissues. This behavior may have substantial benefits since it may allow retaining the desired beneficial therapeutic effects of a drug while minimizing undesirable side effects. Drugs with this mixed agonist/antagonist profile of action are referred to as selective receptor modulators (SRMs). 
Examples:nclude Selective Estrogen Receptor Modulators (SERMs) and Selective Progesterone Receptor Modulators (SPRMs). The mechanism of action of SRMs may vary depending on the chemical structure of the ligand and the receptor involved, however it is thought that many SRMs work by promoting a conformation of the receptor that is closely balanced between agonism and antagonism. In tissues where the concentration of coactivator proteins is higher than corepressors, the equilibrium is shifted in the agonist direction. Conversely in tissues where corepressors dominate, the ligand behaves as an antagonist[22].

The most common mechanism of nuclear receptor action involves direct binding of the nuclear receptor to a DNA hormone response element. This mechanism is referred to as transactivation. However some nuclear receptors not only have the ability to directly bind to DNA, but also to other transcription factors. This binding often results in deactivation of the second transcription factor in a process known as transrepresson.
The classical direct effects of nuclear receptors on gene regulation normally takes hours before a functional effect is seen in cells because of the large number of intermediate steps between nuclear receptor activation and changes in protein expression levels. However it has been observed that some effects from the application of hormones such as estrogen occur within minutes which is inconsistent with the classical mechanism nuclear receptor action. While the molecular target for these non-genomic effects of nuclear receptors has not been conclusively demonstrated, it has been hypothesized that there are variants of nuclear receptors which are membrane associated instead of being localized in the cytosol or nucleus. Furthermore these membrane associated receptors function through alternative signal transduction mechanisms not involving gene regulation [23-24].

Subfamily 1: Thyroid Hormone Receptor-like
Group A: Thyroid hormone receptor (Thyroid hormone) 
o1: Thyroid hormone receptor-α (TRα) 
o2: Thyroid hormone receptor-β (TRβ)
Group B: Retinoic acid receptor (Vitamin A and related compounds) 
o1: Retinoic acid receptor-α (RARα) 
o2: Retinoic acid receptor-β (RARβ)
o3: Retinoic acid receptor-γ (RARγ)
Group C: Peroxisome proliferator-activated receptor (fatty acids, prostaglandins) 
o1: Peroxisome proliferator-activated receptor-α (PPARα )
o2: Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)
o3: Peroxisome proliferator-activated receptor-γ (PPARγ) 
Group D: Rev-ErbA (heme) 
o1: Rev-ErbAα 
o2: Rev-ErbAβ 
Group F: RAR-related orphan receptor (cholesterol) 
o1: RAR-related orphan receptor-α (RORα) 
o2: RAR-related orphan receptor-β (RORβ) 
o3: RAR-related orphan receptor-γ (RORγ)
Group H: Liver X receptor-like (oxysterol) 
o3: Liver X receptor-α (LXRα) 
o2: Liver X receptor-β (LXRβ) 
o4: Farnesoid X receptor (FXR) 
Group I: Vitamin D receptor-like 
o1: Vitamin D receptor (VDR) (vitamin D) 
o2: Pregnane X receptor (PXR (xenobiotics) 
o3: Constitutive androstane receptor (CAR) (androstane) 
Subfamily 2: Retinoid X Receptor-like
Group A: Hepatocyte nuclear factor-4 (HNF4) (fatty acids) 
o1: Hepatocyte nuclear factor-4-α (HNF4α) 
o2: Hepatocyte nuclear factor-4-γ (HNF4γ) 
Group B: Retinoid X receptor (RXRα) (retinoids) 
o1: Retinoid X receptor-α (RXRα) 
o2: Retinoid X receptor-β (RXRβ) 
o3: Retinoid X receptor-γ (RXRγ) 
Group C: Testicular receptor 
o1: Testicular receptor 2 (TR2) 
o2: Testicular receptor 4 (TR4) 
Group E: TLX/PNR 
o1: Human homologue of the Drosophila tailless gene (TLX) 
o2: Photoreceptor cell-specific nuclear receptor (PNR) 
Group F: COUP/EAR 
o1:Chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) 
o2:Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) 
o3:V-erbA-related gene|V-erbA-related (EAR-2 )
 Subfamily 3: Estrogen Receptor-like
Group A: Estrogen receptor (Sex hormones: Estrogen) 
o1: Estrogen receptor-α (ERα) 
o2: Estrogen receptor-β (ERβ) 
Group B: Estrogen related receptor 
o1: Estrogen-related receptor-α (ERRα) 
o2: Estrogen-related receptor-β (ERRβ) 
o3: Estrogen-related receptor-γ (ERRγ) 
Group C: 3-Ketosteroid receptors 
o1: Glucocorticoid receptor (GR) (Cortisol) 
o2: Mineralocorticoid receptor (MR) (Aldosterone) 
o3: Progesterone receptor (PR) (Sex hormones: Progesterone) 
o4: Androgen receptor (AR) (Sex hormones: Testosterone) 
 Subfamily 4: Nerve Growth Factor IB-like
o1: Nerve Growth factor IB (NGFIB) 
o2: Nuclear receptor related 1 (NURR1) 
o3: Neuron-derived orphan receptor 1 (NOR1) 
 Subfamily 5: Steroidogenic Factor-like
Group A: SF1/LRH1 
o1: Steroidogenic factor 1 (SF1)  
o2: Liver receptor homolog-1 (LRH-1)[25-26] 
Subfamily 1: Thyroid Hormone Receptor-like
The thyroid hormone receptor is a type of nuclear receptor that is activated by binding thyroid hormone.
Group A: Thyroid hormone receptor (Thyroid hormone) 
o1: Thyroid hormone receptor-α (TRα) 
o2: Thyroid hormone receptor-β (TRβ)
TR-α1 -widely expressed and especially high expression in cardiac and skeletal muscles 
TR-α2 - widely expressed but unable to bind hormone
TR-β1 -predominately expressed in brain, liver and kidney
TR-β2 -expression primarily limited to the hypothalamus and pituitary
Disease linkage
Certain mutations in the thyroid hormone receptor are associated with thyroid hormone resistance.
Group B: Retinoic acid receptor (Vitamin A and related compounds) 
o1: Retinoic acid receptor-α (RARα) 
o2: Retinoic acid receptor-β (RARβ)
o3: Retinoic acid receptor-γ (RARγ)
The retinoic acid receptor (RAR) is a type of nuclear receptor which is activated by both all-trans retinoic acid and 9-cis retinoic acid. There are three retinoic acid receptors (RAR), RAR-alpha, RAR-beta, and RAR-gamma encoded by the RARA, RARB, RARG genes respectively. Each receptor isoform has several splice variants: two- for alpha, four- for beta and two- for gamma.
As with other type II nuclear receptors, RAR heterodimerizes with RXR and in the absence of ligand, the RAR/RXR dimer binds to hormone response elements complexed with corepressor protein. Binding of agonist ligands to RAR results in dissociation of corepressor and recruitment of coactivator protein which in turn promotes transcription of the downstream target gene into mRNA and eventually protein.
Group C: Peroxisome proliferator-activated receptor (fatty acids, prostaglandins) 
o1: Peroxisome proliferator-activated receptor-α (PPARα )
o2: Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)
o3: Peroxisome proliferator-activated receptor-γ (PPARγ) 
In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, and protein) of higher

Three types of PPARs have been identified: alpha, gamma, and delta (beta). 
 α (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and  others
  β/δ (beta/delta) - expressed in many tissues but markedly in brain,                       adipose   tissue, and skin
   γ (gamma) - although transcribed by the same gene, this PPAR through      alternative splicing is expressed in three forms: 
 γ1 - expressed in virtually all tissues, including heart, muscle, colon,                   
 kidney, pancreas, and spleen
 γ2 - expressed mainly in adipose tissue (30 amino acids longer)
 γ3 - expressed in macrophages, large intestine, white adipose tissue.

PPARs were originally identified in Xenopus frogs as receptors that induce the proliferation of peroxisomes in cells. The first PPAR (PPARα) was discovered during the search of a molecular target for a group of agents then referred to as peroxisome proliferators, as they increased peroxisomal numbers in rodent liver tissue, apart from improving insulin sensitivity. These agents, pharmacologically related to the fibrates were discovered in the early 1980s. When it turned out that PPARs played a much more versatile role in biology, the agents were in turn termed PPAR ligands. The best-known PPAR ligands are the thiazolidinediones; see below for more details.
After PPARδ (delta) was identified in humans in 1992, it turned out to be closely-related to the PPARβ (beta) previously described during the same year in other animals (Xenopus). The name PPARδ is generally used in the US, whereas the use of the PPARβ denomination has remained in Europe where this receptor was initially discovered in Xenopus.
Physiological function:
All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes. These DNA sequences are termed PPREs (peroxisome proliferator hormone response elements). The DNA consensus sequence is AGGTCAXAGGTCA, with X being a random nucleotide. In general, this sequence occurs in the promotor region of a gene, and, when the PPAR binds its ligand, transcription of target genes is increased or decreased, depending on the gene. The RXR also forms a heterodimer with a number of other receptors (e.g., vitamin D and thyroid hormone).
The function of PPARs is modified by the precise shape of their ligand-binding domain (see below) induced by ligand binding and by a number of coactivator and corepressor proteins, the presence of which can stimulate or inhibit receptor function, respectively. 
Endogenous ligands for the PPARs include free fatty acids and eicosanoids. PPARγ is activated by PGJ2 (a prostaglandin). In contrast, PPARα is activated by leukotriene B4.

PPAR gamma                                 
Like other nuclear receptors, PPARs are modular in structure and contain the following functional domains:
 (A/B) N-terminal region
 (C) DBD (DNA-binding domain)
 (D) flexible hinge region
 (E) LBD (ligand binding domain)
 (F) C-terminal region
The DBD contains two zinc finger motifs, which bind to specific sequences of DNA known as hormone response elements when the receptor is activated. The LBD has an extensive secondary structure consisting of 13 alpha helices and a beta sheet Natural and synthetic ligands bind to the LBD, either activating or repressing the receptor.
 PPAR modulator
PPARα and PPARγ are the molecular targets of a number of marketed drugs, e.g. the fibrates. The synthetic chemical perfluorooctanoic acid activates PPARα while the synthetic perfluorononanoic acid activates both PPARα and PPARγ.
 Anti-diabetic drug
 Diabetes mellitus
 Insulin resistance
 Metabolic syndrome[27-30]

 The retinoid X receptor (RXR) is a type of nuclear receptor which is activated by 9-cis retinoic acid.[2] There are three retinoic acid receptors (RXR), RXR-alpha, RXR-beta, and RXR-gamma encoded by the RXRA, RXRB, RXRG genes respectively.
 RXR heterodimerizes with subfamily 1 nuclear receptors including CAR, FXR, LXR, PPAR, PXR, RAR, TR, and VDR.
 As with other type II nuclear receptors, the RXR heterodimer in the absence of ligand is bound to hormone response elements complexed with corepressor protein. Binding of agonist ligands to RXR results in dissociation of corepressor and recruitment of coactivator protein which in turn promotes transcription of the downstream target gene into mRNA and eventually protein[28].

Estrogen receptor refers to a group of receptors which are activated by the hormone 17β-estradiol. 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..
The main function of the estrogen receptor is as a DNA binding transcription factor which regulates gene expression. However the estrogen receptor also has additional functions independent of DNA binding

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 seven domains (listed from the N- to C-terminus; amino acid sequence numbers refer to human ER):
The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand independent regulation.
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 only transactivate transcription when a heterodimer with the functional ERß1 receptor of 59 kDa is formed. The ERß3 receptor was detected at high levels in the testis. The two other ERalpha isoforms are 36 and 46kDa.[4][5] Only in fish, but not in humans, an ERgamma receptor has been described
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 stroma cells and in the hypothalamus.[8] 
The expression of the ERβ protein has been documented in kidney, brain, bone, heart,[9] 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]
 Binding and functional selectivity:
Estrogen receptor bound to the estradiol hormone (top; PDB 1QKU) and to anticancer drug tamoxifen (bottom; 3ERT). These two ligands induce different conformations in the receptor (highlighted in green) which accounts for their different functional activity (agonist vs. antagonist respectively). See the estrogen molecule of the month web page for more details.
The ER's helix 12 domain plays a crucial role in determining interactions with coactivators and corepressors and thereby the respective agonist or antagonist effect of the ligand.[11][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 
Subtype selective estrogen receptor modulators preferentially bind to either the α- or β-subtype of the receptor. Additionally, the different estrogen receptor combinations may respond differently to various ligands which may translate into tissue selective agonistic and antagonistic effects.[13] The ratio of α- to β- subtype concentration has been proposed to play a role in certain diseases.[14]
The concept of selective estrogen receptor modulators is based on the ability to promote ER interactions with different proteins such as transcriptional coactivator or corepressors. Furthermore the ratio of coactivator to corepressor protein varies in different tissues.[15] As a consequence, the same ligand may be an agonist in some tissue (where coactivators predominate) while antagonistic in other tissues (where corepressors dominate). Tamoxifen, for example, is an antagonist in breast and is therefore used as a breast cancer treatment[16] but an ER agonist in bone (thereby preventing osteoporosis) and a partial agonist in the endometrium (increasing the risk of uterine cancer[29-32]

The Nerve Growth factor IB  protein is a member of the Nur nuclear receptor family of intracellular transcription factors and is encoded by the NR4A1 gene NGFIB is involved in cell cycle mediation, inflammation and apoptosis.[4]
The NGFIB protein plays a key role in mediating inflammatory responses in macrophages.[4] In addition, subcellular localization of the NGFIB protein appears to play a key role in the survival and death of cells.[5]
Expression is induced by phytohemagglutinin in human lymphocytes and by serum stimulation of arrested fibroblasts. Translocation of the protein from the nucleus to mitochondria induces apoptosis. Multiple alternatively spliced variants, encoding the same protein, have been identified[33-34]


The steroidogenic factor 1 (SF1) protein is a member of the nuclear receptor family of intracellular transcription factors and is encoded by the NR5A1 gene (nuclear receptor subfamily 5, group A, member 1).[1]
SF-1 is critical regulator of reproduction because its targets include genes at every level of the hypothalamic-pituitary-gonadal axis, as well as many genes involved in gonadal and adrenal steroidogenesis.[35-37]

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36. Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H . "Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice". Neuro Endocrinol. Lett. 2005; 26 (3): 197–203.
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