al. 1986 , Kumar et al. 1987 ). These early discoveries provided the basis for finding new and related genes corresponding to members of the steroid hormone and retinoic acid (RA) families. Searching for a retinoic acid receptor In setting
Martin Petkovich and Pierre Chambon
Vincent Giguère and Ronald M Evans
history of vitamin A and of the unanticipated discovery that its receptor would be a member of the nuclear receptor family now referred to as the retinoic acid receptor (RAR) ( Giguère et al. 1987 ). A companion article in this commemorative issue
Jan Wilde, Maria Erdmann, Michael Mertens, Gabriele Eiselt, and Martin Schmidt
aromatase expression in breast adipose fibroblasts (BAFs). In this study, we show that ligands of the retinoic acid receptors (RARs), all- trans -RA (at-RA) and 9- cis -RA (9 cis -RA), induce aromatase activity in human BAFs via a retinoic acid response
Introduction The retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are the earliest and most intensely studied nuclear receptors (NRs) for their three-dimensional (3D) structures. Both receptor groups bind to retinoic acids (RAs
Russell Snyder and Thomas Thekkumkara
metabolite of preformed vitamin A, exerts its function by binding to nuclear receptors (RXR and RAR) and forming complexes with specific sequences on promoter regions of target genes called retinoic acid response elements ( Mark et al . 2006 ). Therefore
Russell Snyder and Thomas Thekkumkara
for the other agents remains undetermined. As this receptor is regulated in multiple ways, addressing the mechanism of gene transcription is essential to develop better strategies to control the effects of AngII. Retinoic acids, metabolites of
M Schräder, K M Müller, M Becker-André, and C Carlberg
The transcription of vitamin D (VD) responsive genes is regulated by three different nuclear signalling pathways mediated by homodimers of VD receptors (VDRs), heterodimers of VDRs and retinoid X receptors (RXRs) and heterodimers of VDRs with retinoic acid receptors (RARs). Here, the in vitro DNA-binding affinity of all three receptor complexes was shown to be enhanced by the presence of VD. However, the specificity of the three pathways was dictated by the differential affinities of the receptor complexes for VD response elements. Potential response elements were distinguished by the sequence, the separation and the relative orientation of the hexameric core binding motifs. It was found that both VDR-RAR and VDR-RXR heterodimers act functionally on all three response element configurations: direct repeats, palindromes and inverted palindromes. With direct repeats, neither heterodimer type showed a preference for any of the three principal core motifs, (A/G)GGTGA, (A/G)GGTCA and (A/G)GTTCA. However, while they did exhibit preferences for core motifs in palindromes, the spacing requirements were identical for both complexes. Inverted palindromes, however, formed the most specific response elements. A simple model explains a steric link between the optimal spacing of direct repeats and that of inverted palindromes. Taken together, the experimental data and the model provide further criteria for the screening of VD responsive genes.
Y.-J. Y. Wan, L. Wang, and T.-C. J. Wu
The presence of retinoic acid receptor (RAR) α, β and γ mRNA was examined in 16 different kinds of rat tissue using the highly sensitive reverse transcriptase-polymerase chain reaction technique. The data demonstrated that each tissue expressed at least two types of RAR mRNA. Among the three types of RAR mRNA, RAR α was widely expressed in all types of organ and was the dominant form expressed in the gastrointestinal tract. RAR β mRNA was not present in the intestine and spleen. In addition, RAR β mRNA levels were high in the heart, lung, brain, testis and epididymis. RAR γ mRNA was abundant in both male and female reproductive systems, as well as epidermal tissues. The prevalence of each RAR mRNA in the tissues suggests the diverse biological roles of these receptors.
Y-J Y Wan, L Wang, and T-C J Wu
Mouse embryonal carcinoma F9 cells are pluripotent stem cells and differentiate into primitive endodermal cells upon treatment with retinoic acid (RA). We have recently shown that in F9 cells RA regulates gene expression of activin receptor type II (ActR-II), whose ligand is a potent differentiation agent. The present study examined the regulation of the newly cloned activin receptor type IIB (ActR-IIB) gene by RA. F9 cells expressed equal amounts of three ActR-IIB transcripts of 8·0, 7·5 and 4·0 kb. Both 9-cis-RA (c-RA) and all-trans-RA (t-RA) induced ActR-IIB gene expression in a dose-dependent manner. At 10−9 m c-RA exerted no effect, while 10−5 m c-RA increased the 8·0 kb ActR-IIB transcript about sevenfold. In contrast, t-RA induced the 8·0kb ActR-IIB transcript fivefold at 10−9 m and up to eightfold at 10−5 m. The inductive effect on the 8·0 kb transcript was greater than that on the 7·5 kb transcript, and was least effective on the 4·0 kb transcript, suggesting that these three mRNA isoforms may originate from different promoters. Both cycloheximide and actinomycin D inhibited the inductive effect of t-RA on ActR-IIB gene expression, in contrast to ActR-II whose gene expression was not suppressed by cycloheximide but abolished by actinomycin D. Thus, endodermal differentiation of F9 cells is associated with activation of ActR-IIB gene and the mechanisms involved in the regulation of ActR-II and IIB gene expression are different.
decades. Yet, 50 years later, it is the surprising discovery that retinoic acid (RA), an active metabolite of vitamin A, exerts its biological effects via a member of the superfamily of steroid receptors that led to the improbable reunification of vitamin