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  Transforming education transforming IndiaTransforming education transforming India

  LOVELY PROFESSIONAL UNIVERSITY,

PHAGWARA (Punjab)

 Term Paper (BTY-414)

Cell Signaling

TOPIC: Signaling by Nuclear ReceptorsTOPIC: Signaling by Nuclear Receptors

SUBMITTED BY: - SUBMITTED TO:-

Nitish Pathania Mr. Prashant Singh

ROLL NO: - RK7802 A 06

REG. NO.: - 10803694

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ACKNOWLEDGEMENT:

I am extremely grateful and remain indebted to my friends and my guide Mr.  Prashant

Singh  for being a source of inspiration and for their constant support in the Design,

Implementation and Evaluation of this Term Paper. I am thankful to him for their constantconstructive criticism and invaluable suggestions, which benefited me a lot while developing this

 paper on topic “Signalling by NUCLEAR Receptors”. Also they provide me a constant source

of inspiration and motivation for doing hard work while preparing this term paper. Through this

column, it would be my utmost pleasure to express my warm thanks to them for their 

encouragement, co-operation and consent without which I mightn’t be able to accomplish this

work of Term Paper.

I also want to express my gratitude to my God and my parents those are a great source for me of 

inspiration. I am again very thankful to Mr. Prashant Singh who gave me this chance to

express my thoughts with the help of this Term paper regarding the various pathways followed by

nuclear receptors for cellular or signal transduction and also classification of nuclear receptors.

  Nitish Pathania

Contents:

1. Nuclear receptors: overview and classification.

 Nuclear receptor: Introduction

Structure:

2. Signal transduction:

3. Mechanism of action:

4. nuclear receptors four mechanistic classes

5 . Nucl ear Hor mone Recept o rs :

6. The Signaling Pathway of the Steroid Hormone Receptors:

Nuclear receptors: Subfamily: Estrogen Receptor-like

Nuclear receptors enhance our understanding of transcription regulation:

 Nuclear receptor superfamily: Principles of signaling

Theraputic Obstacles and Opportunities

Conclusion

References:

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Nuclear receptors: overview and classification.

Abstract

The nuclear receptor super family comprises a large group of transcription factors that play a key

regulatory role in development and homeostasis of multicellular organisms. A special feature of nuclear receptors is their ability to bind to condensed chromatin templates, which makes them

important initiators of gene transcription. Moreover, the ability of nuclear receptors tosequentially recruit a variety of transcription factors and co regulators to target promoters and toorchestrate the whole process of gene transcription confirms their biological significance and

stimulates intensive research and a high level of scientific interest in this field. In this review, we

summarizes current knowledge regarding the structure and function of nuclear receptors as principal regulators of gene expression. Emphasis is given to the molecular mechanisms of 

nuclear receptor-mediated transcriptional activation and repression including recent progress

made in this area.

Nuclear receptor: Introduction

In the field of molecular biology, nuclear receptors are a class of  proteins found within cells thatare responsible for sensing steroid and thyroid hormones and certain other molecules. In

response, these receptors work 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 happens only when a ligand — a molecule that affects the

receptor's behavior — is present. In more specific terms, 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 that differentiates them from other classes of  receptors is

their ability to directly interact with and control the expression of  genomic DNA. As aconsequence, nuclear receptors play key roles in both embryonic development and adult

homeostasis.

Intracellular Localization

Most NRs are constitutively localized in the nucleus, however, the major proportion of steroid

receptors and other a few other exceptional receptors may be located in the cytoplasm in the

absence of ligand. Nuclear localization of receptors is mainly regulated by protein-protein

interactions such as dimerization with RXRs or co-regulator proteins . In the cytoplasm, NRs are

 bound to heat shock proteins and this association prevents receptor transportation through the

nuclear pores and thus sequesters NRs from binding to DNA . In the nucleus, ligand-mediated

activation of NRs causes redistribution of the receptor to chromatin. Recent evidence which will

  be discussed in more detail has suggested that nuclear localization of some NRs is a cell

signaling- and phosphorylation-dependent event.

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Co-regulator Proteins:

The full activity of NRs depends on a large number of co-regulator proteins that do not bind to

DNA directly, but have a pronounced effect on the outcome of gene expression . In general, non-

liganded NRs form a complex with co-repressor proteins which inhibit transcriptional activity,

often through the recruitment of other cofactor proteins that contain histone deacetylase (HDAC)activity. HDACs alter chromatin structure by promoting chromatin compaction, thus rendering

enhancer regions of genes less accessible to the necessary basal transcriptional machinery.

Activation of NRs by ligand-binding or through phosphorylation induces a conformational

change which results in the dissociation of the co-repressor multiprotein complexes and

subsequent recruitment of co-activator protein complexes that enhance the rate of gene

transcription, often thought the recruitment multiprotein complexes containing histone

acetyltransferase (HAT) activity. Co-regulator proteins thus provide a second level of specificity

in the modulation of gene expression by NRs. Most NR-co-activator proteins identified to date

 preferentially interact with NRs through the C-terminal AF-2 domain via an -LXXLL-motif,

which constitutes a prototypical NR-interaction motif. However, in contrast to most co-activator 

  proteins, the peroxisome proliferator activated receptor gamma co-activator 1 alpha

((PPARGC1a/PGC-1α) interacts not only with the AF-2 region of NRs, but also with the H

region of the selected liver-enriched NRs . In addition to NRs, it has also been shown that the

intrinsic and recruited enzymatic activities of several NR-associated co-factor proteins are

regulated by phosphorylation in a dynamic manner in response to specific signal transduction

 pathways, and this will be discussed later in this review in more detail.

Structure:

 Nuclear receptors are modular in structure and contain the following domains:

All nuclear receptors are composed of a variable N-terminal domain (NTD, A/B); a highly

conserved DNA Binding Domain (DBD, C); a flexible hinge region (D); and a C-terminal Ligand

Binding Domain (LBD, E). The estrogen receptor α is unique in that it contains an additional C-terminal (F) domain with unknown function.[12]

 Nuclear receptors consist of six domains (A-F) based on regions of conserved sequence andfunction. The evolutionarily conserved regions are C and E, and the divergent regions A/B, D,

and F regions.

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  Nuclear receptors contain a variable N-terminal amino acid sequence, (NTD, A/B), which

contains an autonomous transcriptional activation function known as AF-1. The AF-1 shows

weak conservation across the nuclear receptor superfamily and may mediate differential promoter regulation in vivo. The AF-1 sequence functions as a ligand-independent transcriptional activator,

 but can also functionally synergize with AF-2. The NTD is unique to each SHR and has variable

sequence and length. The highly conserved C region harbors the DNA-binding domain thatconfers sequence-specific DNA recognition (DBD, C). Situated between the DBD and the LBDis a linker region, domain D. This region functions as a flexible hinge and contains the nuclear 

localization signal (NLS). The LBD (E) is responsible for the binding of cognate ligand or 

hormone. This domain also contains a ligand-dependent transcriptional activation function (AF-2) necessary for recruiting transcriptional coactivators, which interact with chromatin remodeling

 proteins and the general transcriptional activation machinery. Nuclear receptors may or may not

contain a final domain in the C-terminus, the F region, whose sequence is extremely variable andwhose structure and function are unknown.

The domains starting from the N-terminus (left) to C-terminus (right). NTD = N-terminal

domain, DBD = DNA binding domain. LBD = ligand binding domain. AF = activation function.The steroid hormone receptor abbreviations are ER – estrogen receptor, GR – glucocorticoid

receptor, PR –progesterone receptor, AR – androgen receptor, and MR – mineralocorticoid

receptor. The numbers to the right are the lengths in amino acid residues.

A/B REGION (N-TERMINAL DOMAIN, NTD)

Thus far, there is no elucidation of a crystal structure of an A/B domain. The A/B region in thedifferent NR is highly variable, revealing a very weak evolutionary conservation. The N-terminal

region is the least conservedregion among NR, both in size and sequence. All the nuclear receptors have a unique N-terminal region (NTD) of variable length (100–500 amino acids)

whose 3D structure is unknown.

  NR contains two transactivation functions. One maps to the structurally flexible N-terminal

domain (NTD) and is termed AF-1. The poorly defined N-terminal A/B region contains a

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transcriptional activation function, referred to as activation function 1 (AF-1) that can operate

autonomously. AF-1 can act in a ligand-independent manner when placed outside of the receptor.

Besides the one constitutionally active transactivation region (AF-1), NTD includes severalautonomous transactivation domains (AD). The activation domains (AD) contain transcriptional

activation functions that can activate transcription when fused to a heterologous DNA-binding

domain.

The main determinants for transactivation map to NTD of both the androgen (AR) andglucocorticoid (GR) receptors and while generally there is little sequence conservation between

the different NTD, in contrast to the DBD and LBD, short regions of similarity have been

observed for the AR and GR. The NTD is potentially involved in multiple protein-protein

interactions and the length of this domain has a positive correlation with the activity of AF-1 for different members of the nuclear receptor superfamily.

C REGION (DNA BINDING DOMAIN, DBD):

The DBD consists of a highly conserved residue core located between the N-terminal domain andthe C-terminal ligand-binding domain. The DNA binding domain lies toward the center of themolecule. The amino acid sequence of this domain is similar among different steroid receptors

(56–79% identity). The 3D structure of the DBD has been resolved for a number of nuclear 

receptors. Nuclear magnetic resonance and crystallographic studies for different NR DBD in their DNA uncomplexed and complexed forms with the GR and ER homodimers on their cognate

DNA sequence were the first 3D crystal structure reported.

D REGION (HINGE REGION):

The D region, which is a poorly conserved domain, serves as a hinge between the DBD and the

LBD, allowing rotation of the DBD. The hinge region allows the DBD and LBD to adoptdifferent conformations without creating a steric hindrance. This domain also harbors a nuclear 

localization signal (NLS) or at least some elements of a functional nuclear localization signal.

E REGION (LIGAND BINDING DOMAIN, LBD):

The largest domain is the moderately conserved ligand-binding domain (LBD, E region). Thehallmark of a nuclear receptor is its ligand-binding domain (LBD). This domain is highly

structured, and encodes a wealth of distinct functions most of which operate in a ligand-

dependent manner. The highly conserved region of the nuclear receptor proteins lies near thecarboxyl terminus. The AR C-terminal ligand-binding domain contains about 290 amino acids

and represents about 30% of the receptor. The ligand-binding domains of AR from humans, rats,

and mice are identical, and sequence homology with other steroid receptors ranges between 15%

and 54%.

Signal transduction:

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Overview of signal transduction pathways

• In biology, signal transduction is a mechanism that converts a

mechanical/chemical stimulus to acell into a specific cellular response. Signaltransduction starts with a signal to a receptor, and ends with a change in cell function.

• Transmembrane receptors span the cell membrane, with part of the receptor outside and

  part inside the cell. The chemical signal binds to the outer portion of the receptor,

changing its shape and conveying another signal inside the cell. Some chemical

messengers, such as testosterone, can pass through the cell membrane, and bind directly

to receptors in the cytoplasm or nucleus.

• Sometimes there is a cascade of signals within the cell. With each step of the cascade, the

signal can be amplified, so a small signal can result in a large response. Eventually, the

signal creates a change in the cell, either in the expression of the DNA in the nucleus or in

the activity of enzymes in the cytoplasm.

• These processes can take milliseconds (for ion flux), minutes (for protein- and lipid-

mediated kinase cascades), hours, or days (for gene expression).

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Mechanism of action:

Mechanism nuclear receptor action. This figure depicts the mechanism of a class I nuclear 

receptor (NR) that, in the absence of ligand, is located in the cytosol. Hormone binding to the NR 

triggers dissociation of heat shock proteins (HSP), dimerization, and translocation to the nucleus,

where the NR binds to a specific sequence of  DNA known as a hormone response element

(HRE). The nuclear receptor DNA complex in turn recruits other  proteins that are responsible for 

transcription of downstream DNA into mRNA, which is eventually translated into protein, which

results in a change in cell function.

Mechanism of nuclear receptor action. This figure depicts the mechanism of a class II nuclear 

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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, recruits additional proteins such as RNA polymerase that are

responsible for transcription 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 mechanismof 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 downstream 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 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 (HREs). 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).

Type I nuclear receptors include members of subfamily 3, such as the androgen receptor, estrogen receptors, glucocorticoid receptor , and progesterone receptor .

The nuclear receptor/DNA complex then recruits other proteins that transcribe DNA downstream

from the HRE into messenger RNA and eventually  protein, which causes a change in cellfunction.

Type II

Type II receptors, in contrast to type I, 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 complex thattranscribe DNA into messenger RNA.

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Type II nuclear receptors include principally subfamily 1, for example the retinoic acid receptor, 

retinoid X receptor and thyroid hormone receptor .

Type III

Type III nuclear receptors (principally NR subfamily 2) are similar to type I receptors in that bothclasses 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 III nuclear receptors are orphan receptors, with their endogenous ligands still unknown.

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 foundin most of the NR subfamilies.

Nuclear Hormone Receptors:

 Nuclear hormone receptor proteins form a class of ligand activated proteins that, when bound

to specific sequences of DNA serve as on-off switches for transcription within the cellnucleus. These switches control the development and differentiation of skin, bone and

 behavioral centers in the brain, as well as the continual regulation of reproductive tissues.

Researchers at the Theoretical Biophysics Group study the interaction of some members of the nuclear hormone receptor with DNA as well as their interaction with hormones.

 Nuclear hormone receptors are ligand-activated transcription factors that regulate geneexpression by interacting with specific DNA sequences upstream of their target genes. Asearly as 1968 a two-step mechanism of action was proposed for these receptors based upon

the observation of an inactive and an active state of the receptors. The first step involves

activation through binding of the hormone; the second step consists of receptor binding toDNA and regulation of transcription.

A hormone response element (HRE) is a specific DNA sequence that a receptor recognizeswith markedly increased affinity and typically contains two consensus hexameric half-sites.

The identity of a response element resides in three features: the sequence of the base pairs in

the half-site, the number of base pairs between the half-sites and the relative orientation of 

the two half-sites. Thus each receptor protein dimer that binds the DNA has to recognize thesequence, spacing and orientation of the half-sites within their response element.

The nuclear hormone receptor proteins are composed of several domains which are

differentially conserved between the various receptors and have different roles: a variable N-terminal region, a conserved DNA binding domain (DBD), a variable hinge region, a

conserved ligand binding domain (LBD), and a variable C-terminal region.

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4: Androgen receptor (AR ; NR3C4,  AR) (Sex

hormones: Testosterone)

Structure:

Intracellular steroid hormone receptors share a common structure of four units that are

functionally homologous, so-called "domains":

1. Variable domain: It begins at the N-terminal and is the most variable domain

 between the different receptors.

2.   DNA binding domain: This centrally located highly conserved DNA binding

domain (DBD) consists of two non-repetitive globular motifs  where zinc is coordinated

with four cysteine and nohistidine residues. Their secondary and tertiary structure is

distinct from that of classic zinc fingers. This region controls which gene will beactivated. On DNA it interacts with the hormone response element (HRE).

3.  Hinge region: This area controls the movement of the receptor to the nucleus.

4.   Hormone binding domain: The moderately conserved ligand-binding domain

(LBD) can include a nuclear localization signal, amino-acid sequences capable of binding

chaperones and parts of dimerization interfaces. Such receptors are closely related

to chaperones (namely heat shock proteins hsp90 and hsp56), which are required to

maintain their inactive (but receptive) cytoplasmicconformation. At the end of this

domain is the C-terminal. The terminal connects the molecule to its pair in the

homodimer or heterodimer. It may affect the magnitude of the response.

Depending on their mechanism of action and subcellular distribution, nuclear receptors may be

classified into at least two classes. Nuclear receptors that bind steroid hormones are all classified

as type I receptors. Only type I receptors have a heat shock protein (hsp) associated with the

inactive receptor that will be released when the receptor interacts with the ligand. Type I

receptors may be found in homodimer or heterodimer forms. Type II nuclear receptors have no

hsp, and in contrast to the classical type I receptor are located in the cell nucleus.

There is some evidence that certain steroid hormone receptors can extend through lipid bilayer 

membranes at the surface of cells and might be able to interact with hormones that remain outside

of cells.

Steroid hormone receptors can also function outside of the nucleus and couple to cytoplasmic

signal transduction proteins such as PI3k and Akt kinase.

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Mechanism of action:

Free (that is, unbound) steroids enter the cell cytoplasm and interact with their receptor. In this

  process heat shock protein is dissociated, and the activated receptor-ligand complex is

translocated into the nucleus.

After binding to the ligand (steroid hormone), steroid receptors often form dimers. In the nucleus,

the complex acts as a transcription factor , augmenting or  

suppressing transcription particular genes by its action on DNA.

Type II receptors are located in the nucleus. Thus, their ligands pass through the cell wall and

cytoplasm and enter the nucleus where they activate the receptor without release of hsp. The

activated receptor interacts with the hormone response element and the transcription process is

initiated as with type I receptors.

The cell membrane aldosterone receptor has shown to increase the activity of the

 basolateral  Na/K ATPase, ENaC sodium channels and ROMK potassium channels of 

the principal cell in the distal tubule and cortical collecting duct of nephrons (as well as in the

large bowel and possibly in sweat glands).

A key feature of steroid hormone receptors that is likely to provide a target for therapy confined

to one tissue is the capability of specific parts of the receptor to interact with proteins which have

important roles in regulation of cell physiology.

Nuclear receptors enhance our understanding of transcription regulation:

Receptors for retinoic acid, vitamin D3 and the steroid and thyroid hormones belong to a familyof ligand-activated enhancer-binding factors which are composed of a number of functional

domains required for ligand and DNA binding, nuclear translocation, dimerization and trans-

activation of transcription. Ligand binding, which may promote dissociation of the receptor froma heat shock protein, results in the binding of the ligand-receptor complex as a dimer to its

cognate palindromic responsive element. The mechanism by which the DNA-bound receptor 

activates transcription is unknown but appears to involve more than one trans-activating domain.

Nuclear receptor superfamily: Principles of signaling

 Nuclear receptors (NRs) comprise a family of 49 members that share a common structuralorganization and act as ligand-inducible transcription factors with major (patho)physiological

impact. For some NRs (“orphan receptors”), cognate ligands have not yet been identified or may

not exist. The principles of DNA recognition and ligand binding are well understood from both biochemical and crystal structure analyses. The 3D structures of several DNA-binding domains

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 Nuclear receptor subfamily 3, Estrogen Receptor-like contains Group A: Estrogen receptors

include members 1: Estrogen receptor-α (ERα; NR3A1, ESR1) and 2: Estrogen receptor-β

(ERβ; NR3A2, ESR2); Group B, the Estrogen related receptors include members 1: Estrogenrelated receptor-α (ERRα; NR3B1, ESRRA), 2: Estrogen related receptor-β (ERRβ; NR3B2,

ESRRB), and 3: Estrogen related receptor-γ (ERRγ; NR3B3, ESRRG); and Group C, the 3-

Ketosteroid receptors include members 1: Glucocorticoid receptor (GR; NR3C1) (Cortisol), 2:Mineralocorticoid receptor (MR; NR3C2) (Aldosterone), 3: Progesterone receptor (PR; NR3C3, PGR) (Sex hormones: Progesterone), and 4: Androgen receptor (AR; NR3C4, AR)

(Sex hormones: Testosterone).

Theraputic Obstacles and Opportunities

 NRs control many aspects of biology including development, reproduction, and homeostasis

through target gene activation. The ability to modulate by their activity using fat-solublemolecules makes them extremely attractive drug targets. As our understanding of NR signaling

increases, so does our appreciation of the complexity of their regulation. It is possible that

management of diseases in the future will include therapies that not only target NRs, but also co-

regulator proteins and signaling pathways that are critical in the modulation of their function.

PPARs are the targets of some commonly used drugs in the treatment of hyperlipidemia and type-

2-diabetes. Activation of PPARα by fibrates causes the up-regulation of genes involved in the β-

oxidation of fatty acids.

However, recent evidence has indicated an increased risk of heart attacks with rosiglitazone(marketed as Avandia) and the FDA released a safety alert on the drug in May 2007. Further 

research surrounding the signaling events and co-regulator proteins that affect PPARγ activity in

multiple tissues may be useful in separating the therapeutic effects from the toxic effects of drugs

like rosiglitazone.

One therapeutic challenge and opportunity in development of drugs that target NRs are selective

therapeutic modulators (SRMs). SRMs are NR ligands that exhibit agonistic or antagonistic

activity in a cell- or tissue-dependent manner. The classic SRM is tamoxifen, which can

selectively activate or inhibit estrogen receptor and is commonly used in the treatment of breast

cancer.

SRM-induced alterations in the conformation of NRs may affect the ability of the receptor to bind

to co-regulators or to be phosphorylated. The expression profile of specific co-activator proteins

and co-repressor proteins in a given cell type may affect the relative agonist –vs-antagonist

activity of SRMs.

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Conclusion

It is clear that multiple signaling pathways and phosphorylation events affect NR-mediated

signaling. They modulate protein-protein interactions, sub-cellular localization, DNA-binding,

 protein stability, and transactivation capacity. The situation is further complicated by the fact that

many NR cofactor proteins are themselves modulated by signaling pathways and phosphorylation

events that affect their intrinsic and recruited enzymatic activities. Further investigation into the

role of cell signaling pathways in NR-mediated transcription, and into signaling pathway

crosstalk will be necessary to fully understand the functional implication of these signaling

events. In addition, further characterization of these processes will likely lead to the development

of novel and selective therapeutic molecules for a multitude of indications.

References:

1. http://en.wikipedia.org/wiki/Nuclear_receptor

2. http://www.nature.com/nsmb/journal/v5/n8/full/nsb0898_679.html

3. http://www.citeulike.org/user/ajaymalik/article/3213621

4. http://www.mesomorphosis.com/articles/scally/steroid-hormone-nuclear-

receptors.htm

5. http://www.ks.uiuc.edu/Research/pro_DNA/ster_horm_rec/

6.  http://en.wikipedia.org/wiki/Steroid_hormone_receptor