Corresponding Author

George Zhu

Copy rights

Keywords

Vitamin A; Retinoic acid and retinoid pharmacology; Gene transcription; Molecular model of RA

Abstract

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 also has 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 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 through the autophagy-lysosome 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. An effect to relieve the blockade of pml/RARa-mediated RA dependent promyelocytic differentiation,and retinoic acid(9-cid RA ,ATRA, Am80) in APL therapy(See following figure). Here, RA can overcome the transcrptional repressor activity of pml/RARa. The oncogenic pml/RARa uncover a pathogenic role in leukemogenesis of APL through blocking promyelocytic differentiation; and this oncogenic receptor derivative pml/RARa chimera is locked in their "off" regular mode thereby constitutively repressing transcription of target genes (such as AP-1,PTEN, DAPK2, UP.1, p21WAF/CCKN1A) or key enzymes (such as myeloblastin /proteinase-3, Aurora A kinase) that are critical for differentiation of hematopoietic cells. This is first described in eukaryotes.