Expression in the human brain of retinoic acid induced 1, a protein associated with neurobehavioural disorders

Acknowledgements Funding was provided by the Wellcome Trust and Tenovus Scotland. Prof Fragoso is the recipient of a Post Doctoral Science without Borders grant from the Brazilian National Council for Scientific and Technological Development (CNPq, 37450/2012- 7). We also thank Aberdeen Proteomics for assistance with the western blots as well as the Microscopy and Histology Core Facility at the University of Aberdeen for confocal microscopy.Peer reviewedPublisher PD

Role of retinoic acid receptors in squamous-cell carcinoma in human esophagus

BACKGROUND: Worldwide, cancer in the esophagus ranks among the 10 most common cancers. Alterations of retinoic acid receptors (e.g. RARα, β, γ, and RXRα, β, γ) expression is considered to play an important role in development of squamous-cell carcinoma (SCC), which is the most common esophageal cancer. Alcohol consumption and smoking, which can alter retinoic acid receptor levels, have been identified as key risk factors in the development of carcinoma in the aero-digestive tract. Therefore, the aim of the present study was to evaluate protein levels of retinoic acid receptors (i.e. RARα, β, γ, and RXRβ) in esophageal SCC and surrounding normal tissue of patients with untreated SCC and controls. METHODS: All study participants completed a questionnaire concerning smoking and alcohol drinking habits as well as anthropometrical parameters. Protein levels of RARα, β, γ, and RXRβ were determined by Western Blot in normal esophageal tissue and tissue obtained from SCC of 21 patients with newly diagnosed esophageal SCC and normal esophageal tissue of 10 controls. RESULTS: Protein levels of RARγ were significantly lower by ~68% in SCC compared to normal surrounding tissue in patients with SCC that smoked and/or consumed elevated amounts of alcohol. Furthermore, RARα protein levels were significantly lower (~- 45%) in SCC in comparison to normal esophageal mucosa in patients with elevated alcohol intake. When comparing protein levels of retinoic acid receptors between normal tissue of patients with SCC and controls, RARγ protein levels were found to be significantly higher (~2.7-fold) in normal esophageal tissue of SCC patients than in esophageal tissue obtained from controls. No differences were found for RARα, β, and RXRβ protein levels between normal esophageal tissue of patients and that of controls. CONCLUSION: In conclusion, results of the present study suggest that alterations of retinoic acid receptors protein may contribute in the development of SCC in esophagus and that in some patients life style (e.g. smoking and alcohol consumption) may be a critical component in the alteration of retinoic acid receptor levels in esophagus

The Role of Specific Retinoid Receptors in Sebocyte Growth and Differentiation in Culture11Presented in part at the 1999 Annual Meeting of the Pediatric Academic Societies, San Francisco, CA, May 1–4 (Pediat Res 45 (Part 2): 55A [Abst 313] 1999)

Retinoic acid derivatives (retinoids) exert their pleiotropic effects on cell development through specific nuclear receptors, the retinoic acid receptors and retinoid X receptors. Despite recent progress in understanding the cellular and molecular mechanisms of retinoid activity, it is unknown which of the retinoid receptor pathways are involved in the specific processes of sebocyte growth and development. In this study, we investigated the roles of specific retinoid receptors in sebocyte growth and differentiation, by testing the effects of selective retinoic acid receptor and retinoid X receptor ligands at concentrations between 10−10 M and 10−6 M in a primary rat preputial cell monolayer culture system. Cell growth was determined by number of cells and colonies, and cell differentiation by analysis of lipid-forming colonies. All-trans retinoic acid and selective retinoic acid receptor agonists (CD271 = adapalene, an RAR-β,γ agonist; CD2043 = retinoic acid receptor pan-agonist; and CD336 = Am580, an RAR-α agonist) caused significant decreases in numbers of cells, colonies, and lipid-forming colonies, but with an exception at high doses of all-trans retinoic acid (10−6 M), with which only a small number of colonies grew but they became twice as differentiated as controls (42.2 ± 4.0% vs 22.6 ± 2.7%, mean ± SEM, lipid-forming colonies, p < 0.01). Furthermore, the RAR-β,γ antagonist CD2665 antagonized the suppressive effects of all-trans retinoic acid, adapalene, and CD2043 on both cell growth and differentiation. In contrast, the retinoid X receptor agonist CD2809 increased cell growth slightly and lipid-forming colonies dramatically in a clear dose-related manner to a maximum of 73.7% ± 6.7% at 10−6 M (p < 0.001). Our data suggest that retinoic acid receptors and retinoid X receptors differ in their roles in sebocyte growth and differentiation: (i) retinoic acid receptors, especially the β and/or γ subtypes, mediate both the antiproliferative and antidifferentiative effects of retinoids; (ii) retinoid X receptors mediate prominent differentiative and weak proliferative effects; (iii) the antiproliferative and antidifferentiative effects of all-trans retinoic acid are probably mediated by retinoic acid receptors, whereas its differentiative effect at high dose may be mediated by retinoid X receptors via all-trans retinoic acid metabolism to 9-cis retinoic acid, the natural ligand of retinoid X receptors

Біохімічні аспекти сигнальної функції ретиноїдів при регенерації печінки

Дослiджено роль рецепторiв ретиноєвої кислоти та канонiчної сигналiзацiї ретиноїдiв у регенерацiї печiнки. З використанням моделi клiтинно-специфiчної абляцiї рецепторiв ретиноєвої кислоти шляхом активацiї домiнантної негативної iзоформи (RARαDN) показано, що необхiдною умовою для повноцiнної регенерацiї печiнки, викликаної частковою гепатектомiєю, є реалiзацiя ретиноєвою кислотою її сигнальної функцiї, опосередкованої взаємодiєю зi специфiчними ядерними рецепторами, як складова регенеративної вiдповiдi. Функцiонування ретиноїдзалежного сигнального шляху за участю канонiчних ядерних рецепторiв ретиноєвої кислоти життєво важливе як для печiнки при її гострому ураженнi, так i для органiзму в цiлому.Исследована роль рецепторов ретиноевой кислоты и канонической сигнализации ретиноидов в регенерации печени. С использованием модели клеточно-специфической абляции рецепторов ретиноевой кислоты путем активации доминантной негативной изоформы (RARαDN) показано, что необходимым условием для полноценной регенерации печени, вызванной частичной гепатэктомией, является реализация ретиноевой кислотой ее сигнальной функции, опосредованной взаимодействием со специфическими ядерными рецепторами, как составная регенеративного ответа. Функционирование ретиноидзависимого сигнального пути с участием канонических ядерных рецепторов ретиноевой кислоты жизненно важно как для печени при ее остром поражении, так и для организма в целом.The work is devoted to the role of retinoic acid receptors and retinoid canonical signaling in liver regeneration. Using a model of cell-specific ablation of retinoic acid receptors by activation of dominant negative isoform (RARαDN), it is shown that an essential condition for a full liver regeneration caused by partial hepatectomy is the realization of retinoic acid signaling functions mediated by interaction with specific nuclear receptors as a component of regenerative response. Retinoiddependent signaling pathway functioning, involving canonical nuclear retinoic acid receptors, is vital for the liver during its acute injury and organism as a whole

Developmental expression of retinoic acid receptors (RARs)

Here, I review the developmental expression features of genes encoding the retinoic acid receptors (RARs) and the 'retinoid X' or rexinoid receptors (RXRs). The first detailed expression studies were performed in the mouse over two decades ago, following the cloning of the murine Rar genes. These studies revealed complex expression features at all stages of post-implantation development, one receptor gene (Rara) showing widespread expression, the two others (Rarb and Rarg) with highly regionalized and/or cell type-specific expression in both neural and non-neural tissues. Rxr genes also have either widespread (Rxra, Rxrb), or highly-restricted (Rxrg) expression patterns. Studies performed in zebrafish and Xenopus demonstrated expression of Rar and Rxr genes (both maternal and zygotic), at early pre-gastrulation stages. The eventual characterization of specific enzymes involved in the synthesis of retinoic acid (retinol/retinaldehyde dehydrogenases), or the triggering of its catabolism (CYP26 cytochrome P450s), all of them showing differential expression patterns, led to a clearer understanding of the phenomenons regulated by retinoic acid signaling during development. Functional studies involving targeted gene disruptions in the mouse, and additional approaches such as dominant negative receptor expression in other models, have pinpointed the specific, versus partly redundant, roles of the RARs and RXRs in many developing organ systems. These pleiotropic roles are summarized hereafter in relationship to the receptors’ expression patterns

Regulating Retinoic Acid Availability during Development and Regeneration: The Role of the CYP26 Enzymes.

This review focuses on the role of the Cytochrome p450 subfamily 26 (CYP26) retinoic acid (RA) degrading enzymes during development and regeneration. Cyp26 enzymes, along with retinoic acid synthesising enzymes, are absolutely required for RA homeostasis in these processes by regulating availability of RA for receptor binding and signalling. Cyp26 enzymes are necessary to generate RA gradients and to protect specific tissues from RA signalling. Disruption of RA homeostasis leads to a wide variety of embryonic defects affecting many tissues. Here, the function of CYP26 enzymes is discussed in the context of the RA signalling pathway, enzymatic structure and biochemistry, human genetic disease, and function in development and regeneration as elucidated from animal model studies

Roles of retinoic acid receptors and of Hox genes in the patterning of the teeth and of the jaw skeleton.

Retinoic acid receptors and transcriptional factors encoded by Hox genes play key roles in vertebrate development and belong to an integrated functional network. To investigate the actual functions of these molecules during ontogenesis and in particular in the patterning of the cranial neural crest cells giving rise to the teeth and to the jaw bones, we have generated null mutant mice lacking functional retinoic acid receptors or Hox genes by gene targeting in embryonic stem cells.journal articleresearch support, non-u.s. gov'treview1995 Febimporte

Retinoic acid as a modulator of T cell immunity

Indexación: Scopus. DOAJ.Vitamin A, a generic designation for an array of organic molecules that includes retinal, retinol and retinoic acid, is an essential nutrient needed in a wide array of aspects including the proper functioning of the visual system, maintenance of cell function and differentiation, epithelial surface integrity, erythrocyte production, reproduction, and normal immune function. Vitamin A deficiency is one of the most common micronutrient deficiencies worldwide and is associated with defects in adaptive immunity. Reports from epidemiological studies, clinical trials and experimental studies have clearly demonstrated that vitamin A plays a central role in immunity and that its deficiency is the cause of broad immune alterations including decreased humoral and cellular responses, inadequate immune regulation, weak response to vaccines and poor lymphoid organ development. In this review, we will examine the role of vitamin A in immunity and focus on several aspects of T cell biology such as T helper cell differentiation, function and homing, as well as lymphoid organ development. Further, we will provide an overview of the effects of vitamin A deficiency in the adaptive immune responses and how retinoic acid, through its effect on T cells can fine-tune the balance between tolerance and immunity.http://www.mdpi.com/2072-6643/8/6/34

Function of retinoic acid receptors during embryonic development

Retinoids, the active metabolites of vitamin A, regulate complex gene networks involved in vertebrate morphogenesis, growth, cellular differentiation and homeostasis. Studies performed in vitro, using either acellular systems or transfected cells, have shown that retinoid actions are mediated through heterodimers between the RAR and RXR nuclear receptors. However, in vitro studies indicate what is possible, but not necessarily what is actually occurring in vivo, because they are performed under non-physiological conditions. Therefore, genetic approaches in the animal have been be used to determine the physiological functions of retinoid receptors. Homologous recombination in embryonic stem cells has been used to generate germline null mutations of the RAR- and RXR-coding genes in the mouse. As reviewed here, the generation of such germline mutations, combined with pharmacological approaches to block the RA signalling pathway, has provided genetic evidence that RAR/RXR heterodimers are indeed the functional units transducing the RA signal during prenatal development. However, due to (i) the complexity in “hormonal” signalling through transduction by the multiple RARs and RXRs, (ii) the functional redundancies (possibly artefactually generated by the mutations) within receptor isotypes belonging to a given family, and (iii) in utero or early postnatal lethality of certain germline null mutations, these genetic studies have failed to reveal all the physiological functions of RARs and RXRs, notably in adults. Spatio-temporally-controlled somatic mutations generated in given cell types/tissues and at chosen times during postnatal life, will be required to reveal all the functions of RAR and RXR throughout the lifetime of the mouse