Ce document numérisé est le fruit d'un long travail approuvé par le ...

148
neoplasia.
STRUCTURAL ORGANIZATION OF
PPARs
The nuc1ear receptor subfamily of ppARs [1]
consists of three isotypes named a (NR1C1,
[2]), ~/o (NR1C2), and 'Y (NR1C3) (table 1).
The different members .are encoded by
separate genes. The humanand mouse PPARy
gene transcription generates two transcripts,
yI and 12 resulting from alternative promoter
usage and differential splicing [3-5]. ppAR12
has an additional 29 and 30 NH2-terminal
amino acids sequence in human or mouse
ppAR12 protein respectively. In humans, a
third transcript ppARy3 is generated by
differential promoter usage yielding a protein
identical to PPARyl [5]. Like other nuc1ear
receptors, ppARs have a similar protein
structure consisting of a NH2-terminal NB
domain, a DNA binding domain, a hinge
region and a COOR-terminal ligand-binding
domain. The DNA binding-domain share 85%
similarity within the ppARs subfamily
whereas the ligand-binding domains are only
70% similar within the subfamily members.
Two activating function domains (AF) have
been identified AF-1 contains a
phosphorylation site within a consensus target
sequence for a mitogen-activated protein
kinase (MAPK) within the NB domain of
ppARa and y. AF-2 is located in the COOHterminal
sequence of the ligand-binding
domain ; its presence is necessary for binding
of coactivators who increase the basal
transcription ofPPAR-dependent genes.
TISSUE EXPRESSION
Tissue expression of ppARs is diverse (table
1) [6-9]. PPARa is mainly expressed in tissue
having high fatty acid metabolism and ?igh
peroxisome-dependent activities such as lIver,
kidney, heart or in steroidogenic tissue such as
adrenal gland. Higher expression of ppARy is
restricted to adipose tissue, spleen and
Hervé Schohn et al.
intestine. Lower PPARy expression is
observed in lung, breast and mammary glands.
While ppARy1 distribution correlates with
that of PPARa, PPAR12 expression is
restricted to adipose and colon. PPAR f3/o is
expressed in almost aIl tissue and often at
higher levels than others PPAR isotypes,
except in liver where the receptor expression
is low [7]. The highest expression of
PPAR~/8 is observed in the developing
neural tube and in the epiderma during rat
development [10].
ACTIVATION OF PPARs
Formation ofthe heterodimer
PPARs bind to a specific hormone response
element, named peroxisome proliferator
response element (PPRE), in the promoter of
target genes (figure 1). PPARs action is
mediated through heterodimerization with the
9-cis retinoic acid receptor (RXR) [11, 12].
The PPAR/RXR consensus PPRE is a direct
repeat of the AGGTCA sequence spaced by
one base also referred to DR1 (see [13]). The
precise sequence of PPRE and the spacer
nucleotide are important in the binding of
nuclear receptors as hetero- or homodimers
[14-16]. Other nuclear receptors including
retinoic acid receptor (RAR), COUP-TF1 and
hepatic nuclear factor-4 (HNF-4), bind to
DR!. Nakshatri and Bhat-Nakshatri [16] have
demonstrated that base position within the
consensus sequence and the spacer nucleotide
determine the binding preference of
PPAR!RXR and RARIRXR heterodimers and
HNF4 homodimers on DR1. Moreover, the
promotor context determines whether an
element function as a PPRE or an HNF-4
response element. Thus, the presence and
relative level of promoter-specific
transcription factors will determine the
specificity of transcriptional response level.
PPAR activation has also been shown to occur
not only on the canonical DRI : PPARlRXR
heterodimers binds in vitro to
the palindromic estrogen response element