RARmediated

RAR-mediated signaling refers to cellular responses driven by retinoic acid receptors (RARs), a subfamily of nuclear receptors that mediate the effects of retinoic acid, the active derivative of vitamin A. The three RAR subtypes—RAR alpha (RARα), RAR beta (RARβ), and RAR gamma (RARγ)—form heterodimers with retinoid X receptors (RXRs) and bind to retinoic acid response elements (RAREs) in the promoter regions of target genes. In the presence of retinoic acid, the RAR-RXR complex recruits coactivator proteins and chromatin-modifying enzymes, leading to histone acetylation and transcriptional activation. In the absence of ligand, the receptor associates with corepressor complexes including NCoR/SMRT and histone deacetylases, repressing transcription.

RAR-mediated transcription regulates genes involved in cell differentiation, proliferation, apoptosis, and patterning. In vertebrate development, RA signaling controls anterior-posterior axis formation, limb development, and neurogenesis. In adults, it influences hematopoiesis, skin biology, immune function, and tissue repair. Signaling is tightly controlled by RA synthesis enzymes (such as the ALDH1A family) and RA-degrading enzymes (the CYP26 family).

Therapeutic relevance and challenges: All-trans retinoic acid (ATRA) and related retinoids are used clinically for acute promyelocytic leukemia and certain dermatologic conditions. RA receptors are targets in cancer and regenerative medicine, but signaling can cause teratogenicity and other adverse effects, and resistance can arise through receptor downregulation or altered RA metabolism. Non-genomic RAR actions, including rapid signaling at the cell membrane and cross-talk with other pathways, are an area of ongoing research.