Biology 2382B Lecture Notes - Lecture 9: Retinoid X Receptor, Reagent, Glucocorticoid

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Published on 17 Apr 2013
Lecture 9: Basic Principles of Cell Signalling and GPCR System
Signal Transduction
- Conversion of one signal into another
- Involves growth factors, cytokines, hormones, ECM, neurotransmitters, light, sound etc.
- Incredibly “hot” area; over 300000 papers published
- All aspects of normal development & physiology
- Initiator of diseases – “cancer, heart, diabetes” – turned on too much
- Some of the players: Receptor Tyrosine Kinases (RTK’s), G-protein couples receptors (GPCR’s),
Proto-oncogenes (Ras), Mitogen Activated Protein Kinases (MAPK)
Basic Elements of Cell Signalling
Signal or signalling molecule (ligand, primary messenger)
- Small molecules (epinephrine, acetylcholine, steroids), peptides, hormones etc.
- Large molecules, growth factors, cytokines (proteins)
Intracellular signalling and effector proteins
- G Proteins, protein kinases and phosphates, etc
Second messengers
- Ca++, cAMP, cGMP, IP3, DAG, NO, etc
- cell surface receptors
- intracellular receptors
The second major group of extracellular signals, the small, lipid soluble hormones, including many
different steroid hormones, retinoids, and thyroid hormones – that can diffuse through plasma and nuclear
membranes and interact directly with the transcription factors that they control. The intracellular receptor
for most of these lipid-soluble hormones, which constitute the nuclear receptor super-family, function as
transcription activators when bound to their ligands.
Nuclear Receptors
- all the nuclear receptors have a unique N terminal region of a variable length (100-500 amino
- Portions of this variable region function as activation domains in some nuclear receptors
- The DNA binding domain maps near the center of the primary sequence and has a repeat of the C4
zinc-finger motif
- The hormone binding domain, located near the C terminal region contains a hormone dependant
activation domain
- In some nuclear receptors the hormone binding domain functions as a repression domain in the
absence of ligand
- ER, PR & GR
are in the
- TR & RAR are
in the nucleus
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Nuclear Receptor Response Elements: Hormones
- Response Elements: bind several nuclear receptors
-Heterodimeric nuclear receptors are located exclusively in the nucleus. In thte absence of their
hormone ligand, they repress transcription when bound to their cognate sites in DNA, they do so
by directing hsitone deacetylation
- In ligand – bound conformation, heterodimeric nuclear receptors containing RXR can direct
hyperacetylation of histones in nearby nucleosomes
- In the presence of ligand, ligand binding domains of nuclear receptors also bind to a mediator,
stimulating preinitiation complex assembly
-Homodimeric receptors are found in the cytoplasm in the absence of their ligands. Hormone
binding to these receptors leads to translocation in the nucleus. The hormone dependant
translocation of the homodimeric glucocorticoid receptor (GR) was demonstrated in the
transfection experiments: fusion proteins from expression vectors demonstrate that the hormone
binding domain of the GR mediates translocation to the nucleus in the presence of the hormone
- When the GR isn’t bound to a hormone it is anchored in the cytoplasm as a large protein aggregate
complexed with inhibitor proteins; as long as the receptor is confined to the cytoplasm it can’t
interact with target genes
- Hormone binding of homodimeric receptors releases the inhibitor proteins to allow the receptor to
enter the nucleus where it activates transcription
- The characteristic nucleotide sequences of
the DNA sites that bind nuclear receptors
are called response elements.
- In the absence of hormone, the receptor in
trapped in the cytoplasm by inhibitor
proteins (e.g. HSP90).
- Hormone binding to a nuclear receptor
releases the inhibitor protein, allowing the
receptor to enter the nucleus.
- The receptor binds to a response element of
the target gene and stimulate preinitiation
complex assembly required for transcription
(mRNA synthesis).
- Glucocorticoid is a potent anti-iflammatory
and immunosupressive reagent, also many
other functions
From Extracellular Signal to Cellular Response
- Communication by extracellular signals usually involves the
following steps: Synthesis of the signalling molecule by the
signalling cell and its incorporation into small intracellular
vesicles (1), its release into the extracellular space by
exocytosis (2), and transport of the signal to the target cell (3)
where the signalling molecule binds to a specific cell-surface
receptor protein leading to activation of a receptor (4). The
activated receptor then initiates one or more intracellular
signal transduction pathways (5) leading to specific changes,
usually short term, in cellular function, metabolism, or
movement (6a) or long term changes in gene expression or
development (6b). Termination of the cellular response is
caused by intracellular signalling molecules that inhibit
receptor function (7) and by removal of the extracellular signal
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