30
| 3 | 2011
Klinisk Biokemi i Norden
Nuclear hormone receptors – a family of hormone
dependent transcriptional regulators
Jørn V Sagen
Hormone Laboratory, Haukeland University Hospital, Institute of Medicine, Section for
Endocrinology, University of Bergen, Bergen
Introduction
Hormones play key roles in devel-
opment, cell differentiation, repro-
duction and metabolism, and they
carry out their effects by differ-
ent mechanisms. Hydrophilic or
water-soluble hormones bind to
cell membrane associated recep-
tors followed by activation of second messengers,
whereas small lipophilic hormones are able to dif-
fuse over the cell membrane and bind to intracellular
receptor proteins known as nuclear receptors (1).
The nuclear receptors are important regulators of
many physiological processes, and changes in their
functional properties may be associated with disease.
Importantly, nuclear receptors have also been shown
to be targets of treatment for diseases such as breast
cancer and type 2 diabetes mellitus.
Gene transcription and nuclear hormone receptors
Our genes contain information about the development
and function of the cells. However, the genetic infor-
mation needs to be translated into proteins that execute
the cellular functions encoded by the genes. The infor-
mation contained by deoxyribonucleic acid (DNA) is
transferred to ribonucleic acid (RNA) by gene tran-
scription, a process that is followed by translation in
which a protein is synthesised under the direction
of an mRNA molecule. Gene transcription is a regu-
lated process that involves a multi-subunit complex
consisting of transcription factors, coregulators, and
the basal transcriptional machinery (1, 2). Transcrip-
tion factors are proteins that recognize and bind to
specific DNA sequences. Binding of the transcription
factors typically initiates gene expression by recuitment
of chromatin remodelling protein-complexes which
change the chromatinized or tightly packaged DNA
to a more accessible DNA which enables interactions
with the general transcriptional machinery and RNA
polymerase. Nuclear receptors comprise a family of
ligand-dependent and highly conserved transcription
factors that function in response to endocrine and
dietary signals.
The transcriptional function carried out by the
nuclear receptors are determined by their structural
features which comprise several domains (Figure 1)
(1).
Each nuclear receptor has a highly conserved
and cental DNA-binding domain (DBD) that targets
the receptor to specific binding sites in the promoter
region of a target gene known as Hormone Response
Elements (HRE). Within the DBD there are two
Figure 1.
Structural and functional domains of nuclear hor-
mone receptors. Nuclear receptors contain different functional
domains. The DNA binding- (DBD) domain (C) is a highly
conserved domain. It targets the receptor to specific binding
sites in the promoter region of a target gene called hormone
response elements (HRE) The ligand-binding domain (LBD)
(
E) binds the ligand and comprises the ligand-dependent
transactivation function AF-2 and is also involved in the
interaction with coregulators. A hinge region (D) is localized
between DBD and LBD and contains nuclear localization sig-
nals. In the N-terminus there is variable domain that includes
the ligand-independent transactivation domain AF-1 (A/B),
whereas in the C-terminus there is a variable domain (F) but
its function is less clear.
