Selective Synthetic Ligands for Human Nuclear Retinoic Acid Receptors

Martin, Bernard; Bernardon, Jean-Michel; Cavey, Marie-Thérêse; Bernard, Bruno; Carlavan, Isabelle; Charpentier, Bruno; Pilgrim, W. R.; Shroot, Braham; Reichert, Uwe

doi:10.1159/000211018

Cited by 86 publications

(53 citation statements)

References 13 publications

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“…Nevertheless, the relative binding affinities of these compounds, determined by Crettaz et al are , TTAB, TTNN, Am80 and Am580 in a chloramphenicol-acetyltransferase-receptor-activation assay (Lehmann et al, 1991 ;Graupner et al, 1991) are in agreement with those determined by the absorption assay in the present study. Binding experiments carried out with nuclear extracts from COS-7 cells transfected with vectors expressing RARa (Cavey et al, 1990;Delescluse et al, 1991 ;Martin et al, 1992) show for TTAB as well higher as lower affinities for RARa compared to the data presented in this work. For Am80 and Am580, significantly higher affinities were found than determined in the present communication.…”

Section: Retinoidsupporting

confidence: 44%

In vivo biological activity of retinoids partially correlates to their affinity to recombinant retinoic‐acid receptor α and recombinant‐cellular retinoic‐acid‐binding protein I

Keidel

Szardenings

Mueller

1993

European Journal of Biochemistry

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Several known and some new retinoids were synthesized and their in vivo activity was investigated by an assay, based on induction of alkaline phosphatase in P19 teratocarcinoma cells, human prostate carcinoma cells and primary cultures of neonatal rat heart cells. The assay used in this study was found to be reproducible and useful for rapid screening of retinoids for biological activity. Two newly synthesized compounds exhibit high biological activity. The biological potency of the compounds was compared to their ability to bind to recombinant retinoic-acid receptor a and to cellular retinoic-acid-binding protein I determined by Charsorb-binding assay. mRNA of both retinoic-acid-binding proteins could be detected in the three cell lines investigated. As expected from the number of different retinoic-acid receptors, the results suggest that retinoids do not need to bind retinoic-acid receptor a nor cellular retinoic-acid-binding protein I in order to exhibit biological activity, but most retinoids investigated show a clear correlation between binding to these proteins and their biological activity.

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Section: Retinoidsupporting

confidence: 44%

In vivo biological activity of retinoids partially correlates to their affinity to recombinant retinoic‐acid receptor α and recombinant‐cellular retinoic‐acid‐binding protein I

Keidel

Szardenings

Mueller

1993

European Journal of Biochemistry

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“…3C), indicating that Activin-A treatment is sufficient to induce enhanced chondrogenesis in these cells. To verify the accuracy of our FOP-iMSCs model, we performed a 2D-chonodrogenic assay with retinoic acid receptor-γ agonists (CD437 and R667) (38,39) and confirmed reduction of GAG/DNA in a concentration-dependent manner (SI Appendix, Fig. S8).…”

Section: Enhanced Chondrogenesis Of Fop-imscs Via Bmp and Tgf-β Signamentioning

confidence: 93%

Neofunction of ACVR1 in fibrodysplasia ossificans progressiva

Hino

Ikeya

Horigome

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

259

339

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Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor point mutations in ACVR1 (also known as ALK2), a type I receptor for bone morphogenetic protein (BMP). Two mechanisms of mutated ACVR1 (FOP-ACVR1) have been proposed: ligand-independent constitutive activity and liganddependent hyperactivity in BMP signaling. Here, by using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs), we report a third mechanism, where FOP-ACVR1 abnormally transduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling but not BMP signaling. Activin-A enhanced the chondrogenesis of induced mesenchymal stromal cells derived from FOPiPSCs (FOP-iMSCs) via aberrant activation of BMP signaling in addition to the normal activation of TGF-β signaling in vitro, and induced endochondral ossification of FOP-iMSCs in vivo. These results uncover a novel mechanism of extraskeletal bone formation in FOP and provide a potential new therapeutic strategy for FOP.iPSC | fibrodysplasia ossificans progressiva | heterotopic ossification | BMP | TGF H eterotopic ossification (HO) is defined as bone formation in soft tissue where bone normally does not exist. It can be the result of surgical operations, trauma, or genetic conditions, one of which is fibrodysplasia ossificans progressiva (FOP). FOP is a rare genetic disease characterized by extraskeletal bone formation through endochondral ossification (1-6). The responsive mutation for classic FOP is 617G > A (R206H) in the intracellular glycineand serine-rich (GS) domain (7) of ACVR1 (also known as ALK2), a type I receptor for bone morphogenetic protein (BMP) (8-10). ACVR1 mutations in atypical FOP patients have been found also in other amino acids of the GS domain or protein kinase domain (11,12). Regardless of the mutation site, mutated ACVR1 (FOP-ACVR1) has been shown to activate BMP signaling without exogenous BMP ligands (constitutive activity) and transmit much stronger BMP signaling after ligand stimulation (hyperactivity) (12-25).To reveal the molecular nature of how FOP-ACVR1 activates BMP signaling, cells overexpressing FOP-ACVR1 (12-20), mouse embryonic fibroblasts derived from Alk2 R206H/+ mice (21, 22), and cells from FOP patients, such as stem cells from human exfoliated deciduous teeth (23), FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) (24, 25) and induced mesenchymal stromal cells (iMSCs) from FOP-iPSCs (FOP-iMSCs) (26) have been used as models. Among these cells, Alk2 R206H/+ mouse embryonic fibroblasts and FOP-iMSCs are preferred because of their accessibility and expression level of FOP-ACVR1 using an endogenous promoter. In these cells, however, the constitutive activity and hyperactivity is not strong (within twofold normal levels) (22,26). In addition, despite the essential role of BMP signaling in development (27-31), the pre-and postnatal development and growth of FOP patients are almost normal, and H...

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“…It is to be noted that those two ligands share very similar (if not identical) chemical structure that they also share with the AM580 RARa-selective compound (Gianni et al, 1996;Martin et al, 1992;M Klaus, personal communication). It is thus not surprising that they behave similarly.…”

Section: The Induction Of the Rarb Gene Is A Direct And Speci®c Eect mentioning

confidence: 99%

“…The isoforms-speci®c ligands CD336 (=Am 580; Martin et al, 1992) and CD437 (Reichert et al, 1993) were kindly provided by Dr U Reichert (CIRD; Sophia Antipolis). They were resuspended as 5.10 72 M stock solution in DMSO and subsequently diluted in DMSO.…”

Section: Chemicalsmentioning

confidence: 99%

Role of the different RAR isoforms in controlling the erythrocytic differentiation sequence. Interference with the v-erbA and p135gag-myb-ets nuclear oncogenes

Gandrillon

Samarut

1998

Oncogene

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Little is known as to how the nuclear oncogenes v-erbA and p135gag-myb-ets do transform cells. The elucidation of their molecular mechanisms of action requires the identi®cation of relevant target genes. We analysed the possibility for the RARb gene to represent such a target gene. We ®rst show that the RARb gene induction is a speci®c and direct process, requiring the continous presence of retinoids and under the control of the RARa isoform exclusively. We then show that the expression of either the v-erbA or the p135 gag-myb-ets oncogene is not sucient to block the RARb gene induction. We con®rmed the loss of RARb gene response in certain cell lines but we discarded the possibility that this loss might represent a necessary step for cell lines immortalization. We further show that the RARa isoform activation is necessary and sucient to induce the growth inhibition and the dierentiation stimulation characteristic for the commitment-inducing ability of retinoids in chicken erythrocytic progenitor cells. We therefore propose a model showing that RARa but not RARb is the key mediator for commitment to dierentiation and that it should control two dierent set of genes whose expression is dierentially aected by the verbA and the p135 gag-myb-ets oncogenes.

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Selective Synthetic Ligands for Human Nuclear Retinoic Acid Receptors

Cited by 86 publications

References 13 publications

In vivo biological activity of retinoids partially correlates to their affinity to recombinant retinoic‐acid receptor α and recombinant‐cellular retinoic‐acid‐binding protein I

In vivo biological activity of retinoids partially correlates to their affinity to recombinant retinoic‐acid receptor α and recombinant‐cellular retinoic‐acid‐binding protein I

Neofunction of ACVR1 in fibrodysplasia ossificans progressiva

Role of the different RAR isoforms in controlling the erythrocytic differentiation sequence. Interference with the v-erbA and p135gag-myb-ets nuclear oncogenes

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