il\VOLVEMENT OF RETII\OIC ACID II{ - MSpace at the University of ...

Retinoic acid signaling pathwaybegins at the cellular membrane level. The complexity of
retinoic acid signaling is characteized by the fact that both RAR and RXR receptors
require dimerization partners in order to exhibit their function. The RAR receptors are
charactenzed by obligatory heterodymenzatíon 'with RXR's, while RXRs are found to
homodimenze and heterodimerize with a number of other members of nuclear receptor
super family (Gardner and Chen 1999). Inthe absence of ligands, retinoic acidreceptor
dimers recruit nuclear co-repressor proteins (NCoR, SMRT,Sin3A/B) which in tum
combine with histone deacetylase enzymes resulting in the silencing of the target genes
(Grignani et al. 1998; Heinzel et al. 1997). The silencing is achieved by a deacylation of
histone protein, which results in conformational changes in DNA-histone complex,
thereby limiting the binding of transcriptional factors to targeted genes (Mehta et al.
2003). The conformational changes of DNA-histone complex are chatactenzed by the
changes in N-terminal tails of core histone molecules which makes chromatins more
compact (Bastien and Rochette-Egly 2004).
The binding of ligands, however, results in the receptors conformation change
which causes a release of co-repressors. This change in conformation leads to the
recruitment of co-activators (SRC-I, P-CAF, p300/CBP, ACTR, TIF2), which results in
the histone acetyl transferase induced-acetylation of histone. Acetylation of histone
proteins mediates the relaxation of chromatin and facilitates the positioning of the
transcription machinery at the gene promoter sights @astien and Rochette-Egly 2004).
When activated by ligands, retinoic acid receptors bind to retinoic acid response elements
(RAREs). The relaxation of chromatin and binding of ligand -heterodl'rneric retinoic acid
receptors complex to the RAREs, will result in the activation of RNA polymerase II
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