DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

66 upon binding ligand. Other members of the family such
as the LXR and FXR receptors reside in the nucleus
and are activated by changes in the concentration of
hydrophobic lipid molecules.
SECTION I
GENERAL PRINCIPLES
Nuclear hormone receptors contain four major domains in a
single polypeptide chain. The N-terminal domain can contain an activation
region (AF-1) essential for transcriptional regulation followed
by a very conserved region with two zinc fingers that bind to DNA
(the DNA-binding domain). The N-terminal activation region (AF-1)
is subject to regulation by phosphorylation and other mechanisms
that stimulate or inhibit the overall ability of the nuclear receptor to
activate transcription. The C terminal half of the molecule contains a
hinge region (which can be involved in binding DNA), the domain
responsible for binding the hormone or ligand (the ligand-binding
domain or LBD), and specific sets of amino acid residues for binding
co-activators and co-repressors in a second activation region (AF-
2). The x-ray structures of nuclear hormone receptors show that the
LBD is formed from a bundle of 12 helices and that ligand binding
induces a major conformational change in helix 12 (Privalsky, 2004;
Tontonoz and Spiegelman, 2008). This conformational change also
affects the binding of the co-regulatory proteins essential for activation
of the receptor-DNA complex (Figure 3–12).
When bound to DNA, most of the nuclear hormone receptors
act as dimers—some as homodimers, others as heterodimers. Steroid
hormone receptors such as the glucocorticoid receptor are commonly
homodimers, whereas those for lipids are heterodimers with the
RXR receptor. The receptor dimers bind to repetitive DNA
sequences, either direct repeat sequences or an inverted repeat
termed hormone response elements (HRE) that are specific for each
type of receptor (e.g., AGGTCA half-sites oriented as an inverted
repeat with a three-base spacer for the estrogen receptor). The hormone
response elements in DNA are found upstream of the regulated
genes or in some cases within the regulated genes. An
agonist-bound nuclear hormone receptor often activates a large number
of genes to carry out a program of cellular differentiation or
metabolic regulation. For example, stimulation of the LXR receptor
in hepatocytes activates 29 genes and inhibits 14 others (Kalaany
and Mangelsdorf, 2006).
Co-repressor
RXR OR
Inactive
Co-activator
Co-activator
Active
Co-repressor
Conformational
change
Gene
transcription
Figure 3–12. Diagram of nuclear hormone receptor activation.
A nuclear hormone receptor (OR) is shown in complex with the
retinoic acid receptor (RXR). When an agonist (yellow triangle)
and co-activator bind, a conformational change occurs in helix 12
(black bar) and gene transcription is stimulated. If co-repressors
are bound, activation does not occur. See text for details; see also
Figure 6–13.
An important property of these receptors is that they must
bind their ligand, the appropriate HRE, and a co-regulator (from a
family of over 100 proteins co-regulators) to regulate their target
genes. There are co-activators such as the steroid receptor co-activator
(SRC) family, the p160 family proteins, CARM and CBP/p300 or
PCG-1α, and co-repressors such as the silencing mediator of retinoid
hormone receptor (SMRT) and nuclear hormone receptor co-repressor
(NCor) (Privalsky, 2004). The activity of the nuclear hormone
receptors in a given cell depends not only on the ligand, but the ratio
of co-activators and co-repressors recruited to the complex. Co-activators
recruit enzymes to the transcription complex that modify
chromatin, such as histone acetylase, which serves to unravel
DNA for transcription. Co-repressors recruit proteins such as histone
deacetylase, which keeps DNA tightly packed and inhibits
transcription.
Depending on the chemical nature of the bound ligand and
the combination of co-activatiors and co-repressors recruited to the
complex, nuclear hormone receptors may differentially regulate their
target genes. This property explains the ability of certain drugs to
act as selective modulators of the receptor and gene expression. For
example, compounds such as 17β-estradiol are estrogen receptor
agonists in all tissues, whereas tamoxifen and raloxifene are termed
selective estrogen receptor modulators (SERMs). Tamoxifen and
raloxifene are partial agonists at the estrogen receptor; upon binding,
these agents elicit unique confomations of the ligand-binding
domain. Thus, depending on the specific tissue, different combinations
of co-activators and co-repressors are bound to the receptor-
DNA complex, yielding gene-selective functions. For example,
tamoxifen is an antagonist in breast tissue by virtue of recruiting corepressors
to the transcription factor complex but is an agonist in the
endometrium because it recruits co-activators (Riggs and Hartmann,
2003) (Chapter 40).
APOPTOSIS
The maintenance of many organs requires the continuous
renewal of cells. Examples include mucosal cells
lining the intestine and a variety of cells in the immune
system including T-cells and neutrophils. Cell renewal
requires a balance between survival and expansion of
the cell population, or cell death and removal. The
process by which cells are genetically programmed for
death is termed apoptosis. Apoptosis is a highly regulated
program of biochemical reactions that leads to cell
rounding, shrinking of the cytoplasm, condensation of
the nucleus and nuclear material, and changes in the
cell membrane that eventually lead to presentation of
phosphatidylserine on the outer surface of the cell.
Phosphatidylserine is recognized as a sign of apoptosis
by macrophages, which engulf and phagocytize the
dying cell. Notably, during this process the membrane
of the apoptotic cell remains intact and the cell does not
release its cytoplasm or nuclear material. Thus, unlike
necrotic cell death, the apoptotic process does not initiate
an inflammatory response. Understanding the