Nuclear and Extra-Nuclear Effects of Retinoid Acid Receptors: How They Are Interconnected

Abstract

The nuclear retinoic acid receptors (RAR α, β and γ) and their isoforms are ligand-dependent regulators of transcription Transcription , which mediate the effects of all-trans retinoic acid (RA), the active endogenous metabolite of Vitamin A. They heterodimerize with Retinoid X Receptors (RXRs α, β and γ), and regulate the expression of a battery of target genes Target genes involved in cell growth and differentiation Differentiation . During the two last decades, the description of the crystallographic structures of RARs, the characterization of the polymorphic response elements of their target genes Target genes , and the identification of the multiprotein complexes involved in their transcriptional activity have provided a wealth of information on their pleiotropic effects. However, the regulatory scenario became even more complicated once it was discovered that RARs are phosphoproteins and that RA can activate kinase signaling cascades via a pool of RARs present in membrane lipid rafts. Now it is known that these RA-activated kinases Kinases translocate to the nucleus where they phosphorylate RARs and other retinoid signaling factors. The phosphorylation Phosphorylation state of the RARs dictates whether the transcriptional programs which are known to be induced by RA are facilitated and/or switched on. Thus, kinase signaling pathways appear to be crucial for fine-tuning the appropriate physiological activity of RARs.

Quantitation of retinaldehyde in small biological samples using ultrahigh-performance liquid chromatography tandem mass spectrometry

“…Although this pathway seems quantitatively minor relative vitamin A use in the visual cycle, all vertebrates require atRA for reproduction and embryonic development, growth, and throughout post-natal life to maintain neurological function, energy balance and immune system function[17,18]. Although atRA has been established as the activated retinol metabolite that regulates the systemic functions of vitamin A[19], several other metabolites have been proposed to contribute to the systemic physiological actions of vitamin A. Relatively recently, a hypothesis has been proposed that all- trans -retinal has signaling actions distinct from atRA that attenuate weight gain in females through effects in adipose and liver[20].…”

Doxycycline, metronidazole and isotretinoin: Do they modify microRNA/mRNA expression profiles and function in murine T-cells?

“…RA in combination with RAR binds to retinoic acid responsive elements (RARE) leading to the expression of RA responsive genes (e.g. Socs3, Hoxa1, Hoxa4, CRBPs, and Trim16 )44. Socs3 has been suggested to have different effects in Teffs and Tregs.…”

The neurotoxic effects of vitamin A and retinoids

“…Retinoic acids (mainly alltrans-retinoic acid and 9-cis-retinoic acid) exert its effects by binding to receptors that act as nuclear factors when translocate to nucleus (Napoli 1996). However, an increasing body of evidence shows that retinol and retinoids may trigger specific signals through non-genomic events (Piskunov et al 2014, Rochette-Egly 2015.…”