Activation and Molecular Targets of Peroxisome Proliferator-Activated Receptor- Ligands in Lung Cancer
Figure 1
Activation
pathways for PPAR. PPAR forms a heterodimer with the retinoic acid X receptor (RXR). Activation can occur by thiazolidinidiones
(TZD) such as rosiglitazone or pioglitazone directly binding to the
ligand-binding domain. This results in
the dissociation of corepressors such as NCor and SMRT, and the binding of
coactivators such as p300 and
Src, mediating activation of
transcription. In lung cancer cells,
binding of Wnt7a to its cognate receptor Fzd9 leads to activation of ERK5,
which presumably directly binds to the hinge region of PPAR mediating activation.
Prostacyclin (PGI) and analogs such as iloprost can also lead to PPAR activation, and this may involve ERK5 activation. Conversely, activation of the ERK or JNK
family of MAP kinases can inhibit PPAR activation; this is mediated through direct phosphorylation of
the molecule which alters the ligand binding affinity. Finally, activation of
PPAR/RXR heterodimers may be activated through retinoic acid (RA)
binding to RXR.