The Biochemistry of Retinoic Acid Receptors I Structure Activation and Function at the Molecular Level

This book series, with chapters authored by experts in every aspect of this complex field, unifies the knowledge base and mechanisms currently known in detailed, engaging, well-illustrated, focused chapters that synthesize information for ...

The Biochemistry of Retinoic Acid Receptors I  Structure  Activation  and Function at the Molecular Level

A role for vitamin A in living organisms has been known throughout human history. In the last 100 years, the biochemical nature of vitamin A and its active derivative, retinoic acid, its physiological impact on growth processes and the essential details of its mechanism of action have been revealed by investigations carried out by researchers using vertebrate and more recently invertebrate models to study a multiplicity of processes and conditions, encompassing embryogenesis, postnatal development to old age. A wealth of intercellular interactions, intracellular signaling systems and molecular mechanisms have been described and the overall conclusion is that retinoic acid is essential for life. This book series, with chapters authored by experts in every aspect of this complex field, unifies the knowledge base and mechanisms currently known in detailed, engaging, well-illustrated, focused chapters that synthesize information for each specific area. In view of the recent explosion in this field, it is timely to publish a contemporary, comprehensive, book series recapitulating the most exciting developments in the field and covering fundamental research in molecular mechanisms of vitamin A action, its role in physiology, development and continued well-being and the potential of vitamin A derivatives and synthetic mimetics to serve as therapeutic treatments for cancers and other debilitating human diseases. VOLUME I: Here, we present the first volume of a multi-volume series on Retinoic Acid Signaling that will cover all aspects of this broad and diverse field. One aim of Volume I is to present a compilation of topics related to the biochemistry of nuclear retinoic acid receptors, from their architecture when bound to DNA and associated with their coregulators to their ability to regulate target gene transcription. A second aim is to provide insight into recent advances that have been made in identifying novel targets and non-genomic effects of retinoic acid. Volume I is divided into ten chapters contributed by prominent experts in their respective fields. Each chapter starts with the history of the area of research. Then, the key findings that contributed to development of the field are described, followed by a detailed look at key findings and progress that are being made in current, ongoing research. Each chapter is concluded with a discussion of the relevance of the research and a perspective on missing pieces and lingering gaps that the author recommends will be important in defining future directions in vitamin A research.

The Biochemistry of Retinoid Signaling III

This book covers subjects that have major impacts on society, such as the mechanism of maternal-fetal transfer of vitamin A, and the effects of alcohol on retinoic acid signaling and mammalian embryonic development.

The Biochemistry of Retinoid Signaling III

This book covers subjects that have major impacts on society, such as the mechanism of maternal-fetal transfer of vitamin A, and the effects of alcohol on retinoic acid signaling and mammalian embryonic development. There has been an awareness of the importance of consuming vitamins throughout human history, but empirical studies of their physiological role and mode of action only began about 150 years ago. Since then, the biochemical nature of vitamin A and its active derivative, retinoic acid, have been identified and researchers around the globe have investigated retinoic acid’s physiological function in growth processes and in maintaining life Written by leading experts, this book discusses the latest findings and advances in retinoic acid research. It addresses topics such as the role of retinoic acid signaling in a multitude of processes, including limb, heart and respiratory system development, as well as its role in maintaining postnatal organ systems. This book is a valuable resource for scientists involved in vitamin A/retinoic acid research and readers interested in developmental biology.

Sythesis of Retinoic Acid Analogues Investigations Into Their Ability to Induce Stem Cell Differentation

These compounds are therefore believed to activate the same pathway as the natural metabolite in these cells and that this is responsible for at least some of the observed effects.

Sythesis of Retinoic Acid Analogues   Investigations Into Their Ability to Induce Stem Cell Differentation

Human embryogenesis and ensuing adult homeostasis are directed by the complex interplay of a wide range of exquisitely controlled signalling molecules and pathways. All-trans-retinoic acid (ATRA) is one such important hormone-like compound that regulates a wide range of processes. The endogenous effects of ATRA have the potential to be translated into treatment for numerous clinical indications; however administration at efficacious concentrations is associated with severe side effects. Consequently, a large group of synthetic molecules - known as retinoids - that are structurally and/or functionally analogous to ATRA have been prepared and tested in vitro in the search for a panacea and for use as pharmacological tools to elucidate the retinoid molecular pathway. A small library of stable synthetic retinoids was prepared and their biological activity investigated using TERA2.cl. SP12 human embryonal carcinoma (EC) stem cells. Three compounds, CEB16, CEB17 and CEB18 were found to inhibit cellular proliferation and induce neural and non-neural differentiation. These effects were thoroughly characterised and quantified by monitoring phenotypic changes and the expression of established antigenic markers. Compared to the ability of ATRA and its geometric isomers 9-cis-retinoic acid and 13-cis-retinoic acid, the order of efficacy of induction of neural differentiation was found to be: 13-cis-retinoic acid>9-cis-retinoic acid=ATRA>CEB 18>CEB 17”CEB 16. The molecular mechanism of natural and synthetic retinoid action during TERA2.cl. SP12 differentiation was investigated by performing a detailed temporal analysis of the gene expression of eleven transcripts involved in retinoid transport, activation and metabolism. To date, limited data have been published on the effects of synthetic retinoids on the retinoid pathway during differentiation of human cells and no human studies have examined the activity of synthetic retinoids on the HOX genes. All of the retinoic acid inducible genes examined in this study were found to be modulated in TERA2.cl. SP12 cells in response to both ATRA and two isomeric synthetic retinoids, CEB16 and CEB17, albeit relatively slowly compared to other cell lines. These compounds are therefore believed to activate the same pathway as the natural metabolite in these cells and that this is responsible for at least some of the observed effects. Genes were regulated in a concentration and retinoid dependent manner and this modulation was often multi-phasic demonstrating the complex behaviour of the retinoid system. Interestingly, ATRA was not the most effective inductive agent in all gene analyses. For example 10 [mu]M CEB17 induced up-regulation of RAR-ß more strongly than 10 [mu]m ATRA and 10 [mu]M CEB16 induced the greatest increase in RAR-y transcripts. Further experimentation is required to confirm an apparent relationship between the timing of addition of inductive agent and the expression pattern of several genes. This behaviour highlights the importance of retinoid degradation in culture, which is often overlooked. The three synthetic compounds described extensively herein should be more stable, and thus may be suitable and convenient alternatives for molecular biologists to use in place of ATRA.

Retinoic Acid

In this book, the authors present topical research in the study of the structure, mechanisms and roles in disease of retinoic acid.

Retinoic Acid

Retinoic acid (RA) is a signalling molecule involved in many important pathways in every cell. When RA binds to RA receptors and activates them, cell cycle arrest, differentiation and apoptosis can occur. In this book, the authors present topical research in the study of the structure, mechanisms and roles in disease of retinoic acid. Topics discussed include retinoid signalling in mammalian inner ear development; nuclear receptors for retinoids involved in the control of expression activity of p-glycoprotein; retinoic acid signaling and immunotherapy of cancer; using retinoic acid in molecular medicine and retinol/vitamin A signalling and self-renewal of stem cells.

The Biochemistry of Retinoid Signaling III

This book covers subjects that have major impacts on society, such as the mechanism of maternal-fetal transfer of vitamin A, and the effects of alcohol on retinoic acid signaling and mammalian embryonic development.

The Biochemistry of Retinoid Signaling III

This book covers subjects that have major impacts on society, such as the mechanism of maternal-fetal transfer of vitamin A, and the effects of alcohol on retinoic acid signaling and mammalian embryonic development. There has been an awareness of the importance of consuming vitamins throughout human history, but empirical studies of their physiological role and mode of action only began about 150 years ago. Since then, the biochemical nature of vitamin A and its active derivative, retinoic acid, have been identified and researchers around the globe have investigated retinoic acid’s physiological function in growth processes and in maintaining life Written by leading experts, this book discusses the latest findings and advances in retinoic acid research. It addresses topics such as the role of retinoic acid signaling in a multitude of processes, including limb, heart and respiratory system development, as well as its role in maintaining postnatal organ systems. This book is a valuable resource for scientists involved in vitamin A/retinoic acid research and readers interested in developmental biology.

The Retinoid Receptors and Cellular Retinoic Acid Binding Proteins

The biological functions of retinoic acid (RA) are mediated by two classes of proteins: the nuclear retinoid receptors (retinoid X receptor (RXR) and retinoic acid receptor (RAR)) and the cellular retinoic acid binding proteins (CRABP-I and ...

The Retinoid Receptors and Cellular Retinoic Acid Binding Proteins

The biological functions of retinoic acid (RA) are mediated by two classes of proteins: the nuclear retinoid receptors (retinoid X receptor (RXR) and retinoic acid receptor (RAR)) and the cellular retinoic acid binding proteins (CRABP-I and CRABP-II). RXR's ligand-inducable transcriptional activity is coordinated by Helix 12 (H12), located at its C-terminus. This region has also been postulated to stabilize nuclear receptor-ligand complexes. Here, equilibrium and kinetic parameters governing the interactions between RXR and 9-cis-retinoic acid (9cRA) and with a RXR H12 deletion mutant were measured to examine the role of H12 in stabilizing the RXR-ligand complex. The data reveal that truncation of H12 does not significantly alter the ligand binding affinity of RXR. Surprisingly, H12 was found to facilitate the rates of both the association and the dissociation of the RXR-9cRA complex and hence, these observations point at a novel role for this region. The CRABPs have distinct functions in RA biology. Previous data showed that CRABP-II, but not CRABP-I, enhances RAR transcriptional activity through a process involving direct protein-protein interactions. In this study, the region of CRABP-II that mediates its interaction with RAR was localized. The mechanism underlying the enhancing effects of CRABP-II on the transcriptional activity of RAR was elucidated and the functional consequences of these effects were demonstrated. The CRABP-II surface region containing the residues Gln75, Pro81, and Lys102 was shown to be necessary and sufficient for mediating its interaction with RAR, promoting the holo-RAR complex, and enhancing RAR transcriptional activity. Additionally, CRABP-II was shown to dramatically translocate from cytosol to the nucleus in the presence of RA. Moreover, the observations reveal that the CRABP-II-RAR complex forms in a ligand-dependent fashion and is a short-lived intermediate in the presence of RA. The data establish that enhancement of RAR transcriptional activity by CRABP-II originates from the capacity of CRABP-II to 'channel' RA to RAR. Furthermore, the data demonstrate that CRABP-II enhances the sensitivity of some mammary carcinoma cells to RA-induced cell growth arrest. In summary, the data clearly establish the function of CRABP-II in modulating the RAR-mediated biological activities of RA and the mechanism underlying this effect.

Retinoic Acid inducible Genes CD38 DOK1 and DOK2 and Their Relevance in Differentiation Therapy Retinoic Acid Resistance Syndrome and Drug Resistance

Once in the cell , retinol binds small 21 kDa retinoid binding proteins that are capable ... Retinoic acid signaling is further complicated by the fact that ...

Retinoic Acid inducible Genes CD38  DOK1 and DOK2 and Their Relevance in Differentiation Therapy  Retinoic Acid Resistance Syndrome and Drug Resistance

The functional importance of each gene was determined by stable transfection of cDNA into HL-60 cells followed by examination of cellular characteristics in the presence or absence of atRA or VD3. DOK1 and DOK2 over-expression enhanced growth arrest, G1/G0 cell cycle arrest, differentiation, and ERK1/2 phosphorylation.

The Retinoic Acid Receptors and Cellular Retinoic Acid Binding Protein II

Retinoic acid displays anticarcinogenic activities but the mechanisms by which it exerts these effects remain incompletely understood.

The Retinoic Acid Receptors and Cellular Retinoic Acid Binding Protein II

Retinoic acid displays anticarcinogenic activities but the mechanisms by which it exerts these effects remain incompletely understood. The biological activities of RA are mediated by the ligand-inducible transcription factors retinoic acid receptors (RARs), and the cellular retinoic acid binding proteins (CRABPs). CRABP-II delivers RA from the cytosol to RAR in the nucleus, thereby enhancing the transcriptional activity of the receptor. Consequently, the binding protein sensitizes carcinoma cells in culture and breast tumors in vivo to the growth inhibitory activity of RA. We show that, in MCF-7 mammary carcinoma cells, RA triggers cell cycle arrest after 1-3 days of treatment, and an apoptotic response following 5-7 days of treatment. Growth inhibition is accompanied by increases in expression of cell cycle control and of pro-apoptotic genes. To facilitate studies of RA homeostasis, we developed a novel assay for measuring the concentration of RA in biological samples. Using this method, RA accumulation and rate of degradation in cells were determined. The data demonstrate that MCF-7 cells accumulate RA at concentrations higher than those found in cell media, and that the compound degrades with a half-life on the order of 1-2 hours. The short half-life of RA in these cells enabled the demonstration that upregulation of early RA target genes is sufficient for triggering a subsequent GI arrest response. Two genes, the G1 arrest protein BTG2 and the proapoptotic gene caspase 9, were identified as novel RAR direct targets, and the regulatory elements that mediate this response were localized. In the context of both genes, CRABP-II cooperated with RAR in enhancing transcriptional activation by RA. Surprisingly, additional observations demonstrated that CRABP-II displays anti-apoptotic activities in the absence of RA. These data point at a novel role for the protein, suggesting that, in addition to its ability to enhance the transcriptional activity of RA, CRABP-II possesses a RA-independent function. Finally, we show that RA treatment dramatically reduces the level of expression of CRABP-II, and that this effect is likely exerted by decreasing the stability of its mRNA. This finding constitutes a novel mechanism of negative feedback regulation through which RA dampens its own biological activities.