Retinoic acid Mediated Apoptosis Signaling

Retinoic Acid (RA), a lipophilic molecule and a metabolite of Vitamin-A (all-trans-retinol), affects gene transcription and modulates a wide variety of biological processes such as cell proliferation, differentiation and apoptosis. RA-mediated gene transcription depends on its rate of transport to target cells and the timing of its exposure to Retinoic Acid receptors (RARs) in target tissues. All-trans-Retinoic Acid, the carboxylic acid form of Vitamin-A is of biological significance since it has higher circulating levels than other isomers of RA. Although biologically active ligands for RAR also include 9-cis-Retinoic Acid among others, circulating levels of 9-cis-Retinoic Acid are much lower than those of all-trans-Retinoic Acid. The physiological significance of the isomerization of all-trans-Retinoic Acid to 9-cis-Retinoic Acid and vice versa is yet to be ascertained. RAR are encoded by three separate genes with multiple isoforms α, β and γ, which are generated by alternate promoters and differential splicing. Like all nuclear receptors, RAR have a conserved modular structure consisting of an AF-1 or A/B domain; a zinc finger DNA binding domain (DBD) or C domain; a CoR or D (hinge/corepressor binding) domain; an LBD or AF-2 or E (ligand binding/transcriptional activation) domain; and a variable F (carboxyl terminal) domain. In general, RAR contain six regions from A-F. The DBD binds to the Retinoic Acid response element (RARE) region in the DNA. RAREs consist of direct repeats of the AGG/TTCA motif with a spacer region of (n)25. Vitamin A in the liver is converted to all-trans-Retinoic Acid, diffuses easily to the target tissues through cellular membranes and is translocated to RAR through cellular retinoic acid binding protein (CRABP).The mechanism of all-trans-Retinoic Acid-induced apoptosis is through mitochondrial dysfunction involving TRAIL and its death receptors - the TRAIL receptors (TRAILR). All-trans-Retinoic Acid and interferons function synergistically to activate TRAILR and caspase 8, which in turn increase mitochondrial permeability leading to the release of cytochrome C (CytoC). TRAILR contain functional death domains capable of inducing apoptosis. Binding of TRAIL to TRAILR leads to the recruitment of apoptosis regulator FADD, which functions as a molecular bridge to caspase 8. TRAILR indirectly bind to FADD via the GTP binding protein DAP3. Caspase 8 cleaves BID into tBID, which in turn translocates to the mitochondria and induces cytoC release. CytoC in association with APAF1 activates caspase 9, which causes the cleavage of proteins required for cellular viability, resulting in apoptosis. Caspase 9 also activates caspase3 which directly cleaves downstream substrates like PARPs. Apoptosis by TRAIL and TRAILR is controlled by FLIP.RA functions as an important regulatory signaling molecule for cell growth, differentiation and neurodegeneration both during embryogenesis and in the adult. Retinoic Acid induced apoptosis through death receptors is a potentially promising approach for treatment of Schizophrenia, Alzheimers disease and also for cancer therapy.