Vitamin A and its Derivatives- Retinoic Acid and Retinoid Pharmacology| Biomed Grid

Retinol (Vitamin A) and its derivative retinoic acid (RA) are essential in the control of epithelial cell growth and cellular differentiation. Retinoid is indispensable in vision and RA inhibits the growth of some malignant cells. RA has also striking effect on pattern formation in developing and regenerating limbs, and also a potent morphogen in chick limb bud. Retinoic acid (RA) proved therapeutic benefits in cancer prevention, in skin diseases and in acute promyelocytic leukemia (APL). The elucidation of the molecular basis of vitamin A and its retinoid pharmacology emerged as paradigm for the connection between RA and its structure of RA receptors(RAR), oncogenic pml/RARa as constitutive transcriptional repressor that block myeloid differentiation at promyelocytic phenotype, and the molecular model of retinoic acid action in a special APL. A molecular model is further revised. As an approach to APL treatment, one possible the action of retinoic acid (RA), A consensus sequence (TCAGGTCA motif) has been postulated for thyroid hormone (TRE) and retinoic acid responsive element (RARE)-containing in the promoter region of target genes. High dose of RA-RARE-PML/RARa complexes in intracellular localization appears to relieve repressors from DNA-bound receptor, including the dissociation of corepressor complexes N-CoR, SMRT and HDACs from PML-RARa or partially PML-RARa/RXR. Also release PML/RARa -mediated transcription repression. This transcriptional derepression occurs at RARa target gene promoter. Consquentially, PML-RARa chimera converted receptor from a repressor to a RA-dependent activator of transcription. The resulting pml-RARA oncoprotein proteolytic degradation occurs through the autophagylysosome pathway and the ubiquitin SUMO-proteasome system(UPS) as well as caspase 3, or lysosomal protease (cathepsin D) enzyme or/and EI-like ubiquitin-activating enzyme(UBEIL) induction. Accordingly the expression level of PML-RARa downregulated. PML protein relocalizes into the wild-type nuclear body (PML-NB) configuration or a truncated PML-RARa fusion fragment detected or/and the wild-type RAR upregulated. An effect is to relieve the blockade of pml/RARa-mediated RA dependent promyelocytic differentiation and retinoic acid (9-cis RA, ATRA, Am80) in APL therapy (See figure by Zhu G, January 1991, revised in 2012). Here, RA can overcome the transcriptional repressor activity of pml/RARa.The oncogenic pml/RARa uncover a pathogenic role in leukemogenesis of APL through blocking promyelocytic differentiation. This oncogenic receptor derivative pml/RARa chimera is locked in their “off” regular mode thereby constitutively repressing transcription of target genes or key enzymes (such as AP-1, PTEN, DAPK2, UP.1, p21WAF/CCKN1A) that are critical for differentiation of hematopoietic cells. This is first described in eukaryotes.