Fig. 1

ATRA uptake inside the cell and intra-cellular mechanism of action. Dietary Vitamin-A is released into the blood as retinol which is complexed to RBP4 (Retinol Binding Protein 4). The cellular uptake of retinol is mediated by STRA6 (Stimulated by Retinoic Acid 6). Intracellular retinol is either stored as an ester or further oxidized into retinaldehyde by ADHs (Alcohol Dehydrogenases) or RDHs (Retinol Dehydrogenases). Retinaldehyde is further transformed into ATRA by RALDHs (Retinaldehyde Dehydrogenases). In the cytosol, ATRA can be transported to the nucleus by CRABP2 (Cellular Retinoic Acid Binding Protein 2) or by FABP5 (Fatty Acid Binding Protein 5). By converse, ATRA is targeted to degradation by CRABP1 (Cellular Retinoic Acid Binding Protein 2). In the nucleus, ATRA binds to one of the indicated SNRs (Steroid Nuclear Receptors) generating an active transcriptional complex which interacts with the DNA regulatory regions of target genes containing RAREs (Retinoic Acid Responsive Elements) or PPREs (Peroxisome Proliferator Responsive Elements). In breast cancer cells, ATRA binding to the SNR heterodimers RAR/RXR (Retinoic Acid Receptor/Retinoic X receptor) triggers growth inhibitory/differentiating effects while ATRA binding to PPAR/RXR heterodimers (Peroxisome Proliferator Activated Receptor) sustains proliferation. ATRA exerts non-genomic effects via interactions with membrane bound RARs. These interactions activate MAP-kinase cascades which concur to the activation of RARE dependent target genes. Retinol bound RBP4 can also trigger intra-cellular signals by activating the STAT3/STAT5 transcription factors