Retinoic acid

Abstract

What is retinoic acid? Retinoic acid is a lipophilic molecule of low molecular weight (300 Da). Retinoic acid is synthesized from vitamin A (retinol) and found in embryos and adult vertebrates. Because animals are unable to produce vitamin A, they obtain this vitamin in the form of carotenoids from plants or retinyl esters derived from animal products. How is retinoic acid produced? In vertebrates, vitamin A, in the form of retinyl esters, is stored mainly in the liver as well as in the lungs, kidneys and bone marrow. Retinol, bound to the retinol-binding protein (RBP), enters the circulatory system in order to reach cells that require retinoic acid. The retinol–RBP complex enters the cells through the RBP receptor (STRA6). Within the cells, retinol is metabolized in a reversible step to retinal by the retinol or alcohol dehydrogenases (RODHs or ADHs) and then in an irreversible manner to retinoic acid by the retinal dehydrogenases (RALDHs). In the cytoplasm, retinoic acid is associated with the cellular retinoic acid-binding protein (CRABP). And what does it do? Simply speaking, retinoic acid functions to regulate gene expression (Figure 1). In cells, retinoic acid enters the nucleus where it binds to heterodimers formed by two different classes of nuclear receptors: Retinoic acid receptors (RARs) and retinoid X receptor (RXRs). The receptor heterodimers are bound to a specific DNA sequence known as the retinoic acid-response element (RARE) and upon retinoic acid binding, recruits co-activators (including histone acetyltransferase (HAT)), leading to transcription activation of specific retinoic acid-regulated genes. How many RARs and RXRs are there? In most vertebrates, there are three RARs (α, β and γ) and three RXRs (α, β and γ), all of which can have multiple isoforms, leading to large numbers of possible receptor combinations. How is the retinoic acid ‘signal’ turned off? In the cytoplasm, retinoic acid can be catabolized by the cytochrome P450 enzyme (CYP26) into inactive compounds that are then excreted. In the absence of retinoic acid, the RAR/RXR heterodimers bound to their target sequences recruit the nuclear receptor co-repressor complex NCOR/Sin3A/HDAC (histone deacetylase), inhibiting transcription activation. What does retinoic acid do? In adults, vitamin A and its retinoid derivatives play significant roles in a number of processes, such as vision, learning and memory, immune function, reproduction as well as the maintenance of epithelial function and differentiation. In the hippocampus, retinoic acid plays important physiological roles in synaptic plasticity, learning and memory, and adult neurogenesis. In the retina, retinoic acid acts as a light-signaling neuromodulator and regulates gap junction-mediated coupling of retinal neurons. It has also been implicated in the control of sleep and the circadian clock. Why are developmental biologists so obsessed with retinoic acid? This simple molecule has been implicated in the control of many aspects of embryo development that include cranio-facial morphogenesis, neuronal differentiation, eye, limb, lung, kidney and heart development. The patterning of the antero-posterior embryo body axis is also directly regulated by retinoic acid, which controls the expression of several HOX genes through RAREs in their regulatory/enhancer regions. Are there any human diseases related to retinoic acid deficiency? Reduction of vitamin A levels in the diet can lead to a debilitating immune system, anemia or blindness. During pregnancy, insufficient levels of vitamin A lead to fetal vitamin A deficiency-induced syndrome. This results in developmental defects exhibiting many common features with those observed in the RAR/RXR mutations in mouse, including cranio-facial and eye abnormalities. Retinoic acid as an anticancer drug…? Acute promyelocytic leukaemia is caused by a chromosomal translocation that fuses the promyelocytic leukaemia gene (PML) on chromosome 15 with the RARα gene on chromosome 17. The PML-RARα fusion protein leads to a recruitment of co-repressor complexes that epigenetically silence gene expression. Differentiation therapy with retinoic acid is being used in combination with chemotherapy for the treatment of patients with acute promyelocytic leukaemia, resulting in a 70-80% cure rate. Retinoic acidVilhais-Neto et al.Current BiologyApril 08, 2008In Brief(Current Biology 18, R191–R192, March 11, 2008) Full-Text PDF Open Archive