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Peroxisome proliferator-activated receptors are key regulators in cell differentiation 157
that ppARy agonists are of clinical
importance in limiting cancer development
even though this benefical effect depend on
cancer type and treatment used [167, 168,
193].
In addition, genetic modifications affecting
:ppAR genes are also present. A truncated
ppARa protein has been described that lacks
exon 6 in hepatoblastoma cells [194]. Its
transcriptionallevel corresponds to 20-50% of
ppARa mRNA and it 10caJizes exclusively in
the cytoplasm. This truncated ppARa protein
is a dominant negative inhibitor of wild type
PPARa protein activity [194]. Likewise, a
frameshift mutation has been described for the
PPARy gene in sporadic colon cancer
affecting exon 3 and subsequently provides a
truncated protein without ligand-binding
domain [170].
Moreover, treatment with clofibrate increases
the translational level of a ppARy2 truncated
protein in rat liver [195]. This truncated
protein specifically localizes in the
mitochondrial matrix. Its translational level
may depend on PPARa activation [196]. The
significance of these truncated proteins is
however not established. Finally, a fusion
protein, PAX8-PPARyl, has been described in
thyroid follicular carcinoma [197]. This
chimeric protein corresponds to chromosomic
translocation t(2;3)q(13;25). PAX8 promotes
development ofthyroid epithelium [198]. The
resulting fusion protein is a dominant negative
inhibitor ofPPARy1 activity [197].
CONCLUSION
ppARs participate to cell differentiation and
may play important roles in patho10gic
processes including atherosclerosis and
cancer. Discovery of ppAR agonists has often
permit to understand the function of these
transcription factors in human physiology and
to find PPARa and PPARy-dependent target
genes. However, little is know about ppARo
target genes. The main difficulty in this field
is the absence of synthetic ligand. An other
interesting challenge cornes from the use of
ppAR agonists especially ppARy ligands,
prostaglandin J2 derivatives, which interferre
with NF1d3 signaling pathway [132, 133].
Data demonstrate that synthetic ppARy
ligands could interplay of signaling pathway
affecting the synthesis of pro-inflammatory
prostaglandins, the synthesis of ppAR ligands
and consequently they may affect re1ease or
metabo1ic transformation of fatty acids within
the cell. In addition, the net effect of
prostaglandin J2 treatment in multiple cell
pathologic process need to be clarify. Thus the
know1edge of the different connections in
ppARs ligand signa1ing pathways is of great
importance for human physiology.
ABREVIATIONS MAPK, mitogenactivated
protein kinase ppAR, peroxisome
pro1iferator-activated receptor PPRE,
peroxisome proliferator response element;
RXR, 9-cis retinoic acid receptor
AKNOWLEDGMENTS
We thank Pr Oliver Nusse for reading the
manuscript.
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