Conformationally Defined 6-s-trans-Retinoic Acid Analogs. 2. Selective Agonists for Nuclear Receptor Binding and Transcriptional Activity

1995 ◽  
Vol 38 (13) ◽  
pp. 2302-2310 ◽  
Author(s):  
Muzaffar Alam ◽  
Valdimir Zhestkov ◽  
Brahma P. Sani ◽  
Pratap Venepally ◽  
Arthur A. Levin ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Nuclear Receptor ◽  
Receptor Binding ◽  
Transcriptional Activity ◽  
Trans Retinoic Acid ◽  
Selective Agonists

The Role of Transcriptional Coactivator TRAP220/MED1 in Nuclear Receptor-Mediated Myelomonocytic Differentiation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2727-2727
Author(s):  
Mitsuhiro Ito ◽  
Norinaga Urahama ◽  
Akiko Sada ◽  
Kimikazu Yakushijin ◽  
Katsuya Yamamoto ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Precursor Cells ◽  
Mediator Complex ◽  
Dihydroxyvitamin D3 ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Hematopoietic Precursor

Abstract The TRAP/Mediator complex, the metazoan counterpart of the yeast Mediator complex, is master transcriptional regulatory complex composed of approximately 30 subunits. It was originally isolated as a thyroid hormone receptor (TR)-associated protein (TRAP) complex that mediates TR-activated transcription from DNA templates in vitro and probably acts in vivo after the action of other receptor-interacting coactivators involved in chromatin remodeling. The TRAP220/MED1 subunit of the TRAP/Mediator complex is proposed to act on a variety of major and specific biological events, including growth, differentiation and homeostasis, through physical interaction with nuclear receptors. The vitamin D receptor (VDR) and retinoic acid receptor (RAR), coupled with retinoid X receptor (RXR), are nuclear receptors which have important roles for monopoiesis and granulopoiesis, respectively. In this study, we present the functional role of TRAP220/MED1 in nuclear receptor-mediated monopoiesis and granulopoiesis. Since TRAP220 knockout (Trap220-/-) mice were mortalities during the early embryonic period before definitive hematopoiesis within the hepatic primordia becomes dominant, the function of TRAP220/MED1 in adult hematopoiesis was mostly unknown. However, these embryos appeared to have normal composition of nucleated erythroid cells. Therefore, the E9.0 yolk sac-derived hematopoietic precursor cells were used to differentiate into definitive hematopoietic colony forming units within the methylcellulose blood cell culture. The number of monocytic colonies (CFU-M) was significantly lower in knockouts than in wild type controls, while the numbers of other types of colonies (CFU-GEMM, CFU-GM, CFU-G and CFU-E) were comparable. Hence, TRAP220/MED1 appeared to be indispensable for optimal monocytic differentiation. Next, the HL-60 acute promyelocytic leukemia cells were used to elucidate directly and mechanistically the roles of TRAP220/MED1 in RAR- and VDR-dependent differentiation of the hematopoietic precursor cells into granulocytic and monocytic lineage cells. The expression of the TRAP220/MED1 subunit as well as other TRAP/Mediator subunits was induced when the cells were treated with their ligands, all-trans retinoic acid and 1,25-dihydroxyvitamin D3. Flow cytometric analyses showed that HL-60 cells, wherein TRAP220/MED1 was down-regulated, did not differentiate efficiently into monocytes and granulocytes by stimulation with 1,25-dihydroxyvitamin D3 and all-trans retinoic acid, correspondingly. The expression of direct target genes of VDR or RAR, as well as the differentiation marker genes, was low in the knockdown cells by stimulation with these ligands. In contrast, 12-O-tetradecanoylphorbol-13-acetate (TPA)- and dimethylsulphoxide (DMSO)-mediated monocytic and myeloid differentiation, which bypasses nuclear receptor-mediated signaling pathways, was not affected in knockdown cells. Collectively, these results indicated an indispensable role of TRAP220/MED1 in the optimal VDR- and RAR-mediated myelomonocytic differentiation processes in mammalian hematopoiesis.

Cooperative Action of 1alpha,25-Dihydroxyvitamin D3 and Retinoic Acid in NB4 Acute Promyelocytic Leukemia Cell Differentiation Is Transcriptionally Controlled.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4247-4247
Author(s):  
Jean-Noel Bastie ◽  
Nicole Balitrand ◽  
Isabelle Guillemot ◽  
Christine Chomienne ◽  
Laurent Delva
Keyword(s):  
Retinoic Acid ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Leukemia Cell ◽  
Leukemic Cells ◽  
Dihydroxyvitamin D3 ◽  
Nb4 Cells ◽  
Cooperative Action ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract All-trans-retinoic acid (RA) and 1alpha,25-dihydroxyvitamin D3 (1,25D3) are involved in the control of hematopoiesis and have been suggested to play a role in cellular differentiation and are as such potent inducers of differentiation of myeloid leukemia cells. In this study, we have shown that in promyelocytic NB4 cells, addition of 1,25D3 enhances terminal granulocytic RA-dependent differentiation concomitant with the enhanced activation of the RA-transcriptional activity through an RARbeta promoter. By EMSA and ChIP assays, we further demonstrate that while both VDR and RAR are bound to the RARbeta promoter in NB4 cells, addition of 1,25D3 increases VDR binding to this promoter while that of RA induces the release of VDR and increases the binding of RAR. Thus, contrary to normal myeloid cells, 1,25D3 does not act as a transrepressor of RA-transcriptional activity in leukemic cells suggesting that transcriptional regulation of RA-target genes may be modified in malignant cells. In promyelocytic leukemic cells the combination of 1,25D3 and RA results in both enhanced transactivation and differentiation.

Dichotomy of All-Trans Retinoic Acid Inducing Signals for Adult T-Cell Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4803-4803
Author(s):  
Yasuhiro Maeda ◽  
Terufumi Yamaguchi ◽  
Yasuki Hijikata ◽  
Yasuyoshi Morita ◽  
Chikara Hirase ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
T Cell ◽  
Cell Lines ◽  
Transcriptional Activity ◽  
Cell Leukemia ◽  
Proviral Dna ◽  
Adult T Cell Leukemia ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
T Cell Lines

Abstract We previously reported that all-trans retinoic acid (ATRA) inhibits growth in HTLV-1-positive T-cell lines and fresh cells from patients with adult T-cell leukemia. However, the mechanism of this inhibition is not clear. In the present study, we observed that NF-κB transcriptional activity as well as cell growth decreased significantly in HTLV-1-positive T-cell lines in the presence of ATRA. Furthermore, we observed that ATRA reduced HTLV-1 proviral DNA, HTLV-1 genes (gag, tax or pol mRNA) using the real time quantitative polymerase chain reaction. SIL-2R was reduced by ATRA in both protein level (culture supernantant) and mRNA level in HTLV-1-positive T-cell lines. Interestingly, ATRA significantly inhibited RT activity similar to azidothimidine (AZT) in HTLV-1-positive T-cell lines. Moreover, AZT was inhibitory of proviral DNA but not NF-kB transcriptional activity and sIL-2R on HTLV-1, however ATRA was inhibitory of NF-kB, proviral DNA and sIL-2R on HTLV-1. These results suggested that the decrease of sIL-2R induced by ATRA may be caused by the actions of a NF-kB inhibitor acting on the NF-kB/sIL-2R signal pathway. These results suggested that ATRA could have two roles, as a NF-kB inhibitor and as a RT inhibitor.

All-trans retinoic acid is a ligand for the orphan nuclear receptor RORβ

2003 ◽  
Vol 10 (10) ◽  
pp. 820-825 ◽  
Author(s):  
Catherine Stehlin-Gaon ◽  
Dominica Willmann ◽  
Denis Zeyer ◽  
Sarah Sanglier ◽  
Alain Van Dorsselaer ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Nuclear Receptor ◽  
Orphan Nuclear Receptor ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Interactions of STAT5b-RARα, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2637-2646 ◽  
Author(s):  
Shuo Dong ◽  
David J. Tweardy
Keyword(s):  
Retinoic Acid ◽  
Fusion Protein ◽  
Acute Promyelocytic Leukemia ◽  
Nuclear Receptor ◽  
Fusion Proteins ◽  
Transcriptional Activity ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Maturation Arrest ◽  
Acid Receptor

Abstract Signal transducer and activator of transcription (STAT) 5b-retinoic acid receptor (RAR) α is the fifth fusion protein identified in acute promyelocytic leukemia (APL). Initially described in a patient with all-trans retinoic acid (ATRA)–unresponsive disease, STAT5b-RARα resulted from an interstitial deletion on chromosome 17. To determine the molecular mechanisms of myeloid leukemogenesis and maturation arrest in STAT5b-RARα+ APL and its unresponsiveness to ATRA, we examined the effect of STAT5b-RARα on the activity of myeloid transcription factors including RARα/retinoid X receptor (RXR) α, STAT3, and STAT5 as well as its molecular interactions with the nuclear receptor corepressor, SMRT, and nuclear receptor coactivator, TRAM-1. STAT5b-RARα bound to retinoic acid response elements (RAREs) both as a homodimer and as a heterodimer with RXRα and inhibited wild-type RARα/RXRα transactivation. Although STAT5b-RARα had no effect on ligand-induced STAT5b activation, it enhanced interleukin 6–induced STAT3-dependent reporter activity, an effect shared by other APL fusion proteins including promyelocytic leukemia-RARα and promyelocytic leukemia zinc finger (PLZF)–RARα. SMRT was released from STAT5b-RARα/SMRT complexes by ATRA at 10−6 M, whereas TRAM-1 became associated with STAT5b-RARα at 10−7 M. The coiled-coil domain of STAT5b was required for formation of STAT5b-RARα homodimers, for the inhibition of RARα/RXRα transcriptional activity, and for stability of the STAT5b-RARα/SMRT complex. Thus, STAT5b-RARα contributes to myeloid maturation arrest by binding to RARE as either a homodimer or as a heterodimer with RXRα resulting in the recruitment of SMRT and inhibition of RARα/RXRα transcriptional activity. In addition, STAT5b-RARα and other APL fusion proteins may contribute to leukemogenesis by interaction with the STAT3 oncogene pathway.

scholarly journals Spermatogonia Differentiation Requires Retinoic Acid Receptor γ

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 438-449 ◽  
Author(s):  
Aurore Gely-Pernot ◽  
Mathilde Raverdeau ◽  
Catherine Célébi ◽  
Christine Dennefeld ◽  
Betty Feret ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Nuclear Receptor ◽  
Sertoli Cells ◽  
Retinoic Acid Receptor ◽  
Vitamin A Deficiency ◽  
Seminiferous Tubules ◽  
Wild Type ◽  
Differentiation Markers ◽  
Selective Agonists

Vitamin A is instrumental to mammalian reproduction. Its metabolite, retinoic acid (RA), acts in a hormone-like manner through binding to and activating three nuclear receptor isotypes, RA receptor (RAR)α (RARA), RARβ, and RARγ (RARG). Here, we show that 1) RARG is expressed by A aligned (Aal) spermatogonia, as well as during the transition from Aal to A1 spermatogonia, which is known to require RA; and 2) ablation of Rarg, either in the whole mouse or specifically in spermatogonia, does not affect meiosis and spermiogenesis but impairs the Aal to A1 transition in the course of some of the seminiferous epithelium cycles. Upon ageing, this phenomenon yields seminiferous tubules containing only spermatogonia and Sertoli cells. Altogether, our findings indicate that RARG cell-autonomously transduces, in undifferentiated spermatogonia of adult testes, a RA signal critical for spermatogenesis. During the prepubertal spermatogenic wave, the loss of RARG function can however be compensated by RARA, as indicated by the normal timing of appearance of meiotic cells in Rarg-null testes. Accordingly, RARG- and RARA-selective agonists are both able to stimulate Stra8 expression in wild-type prepubertal testes. Interestingly, inactivation of Rarg does not impair expression of the spermatogonia differentiation markers Kit and Stra8, contrary to vitamin A deficiency. This latter observation supports the notion that the RA-signaling pathway previously shown to operate in Sertoli cells also participates in spermatogonia differentiation.

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