Synthesis and biological activity of high-affinity retinoic acid receptor antagonists

Johnson, A. T. Charlie; Wang, Liming; Standeven, Andrew M.; Escobar, Maria; Chandraratna, Roshantha A.S.

doi:10.1016/s0968-0896(99)00055-3

Cited by 48 publications

(32 citation statements)

References 42 publications

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“…To test whether suppression of downstream RA signaling is critical to maintaining primitive hematopoietic cells, CD34 + CD38 − cells from normal human bone marrow were cultured in serum-free conditions containing thrombopoietin, stem-cell factor, and Flt3-ligand (TSF) with and without the pan-RAR inhibitor AGN194310 (AGN) (11,23). Culture of the CD34 + CD38 − cells with TSF rapidly generated CFU-Cs, whose numbers reached a plateau at approximately day 21 (Fig.…”

Section: Inhibition Of Ra Signaling Results In Expansion Of Primitivementioning

confidence: 99%

Regulation of human hematopoietic stem cell self-renewal by the microenvironment’s control of retinoic acid signaling

Ghiaur

Yegnasubramanian

Perkins

et al. 2013

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

121

114

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Significance Mechanisms that control physiologic hematopoietic stem-cell (HSC) self-renewal remain largely unknown. Inhibition of retinoic acid (RA) signaling in HSCs maintained their primitive phenotype and function, and promoted their self-renewal. Moreover, bone marrow stroma’s expression of the cytochrome P450 retinoid-inactivating enzyme, CYP26, allowed HSC self-renewal by maintaining an environment low in retinoids. Thus, HSCs appear to be intrinsically programmed to undergo RA-mediated differentiation unless prevented from doing so by bone marrow niche CYP26. Modulation of RA signaling also holds promise for clinical HSC expansion.

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Section: Inhibition Of Ra Signaling Results In Expansion Of Primitivementioning

confidence: 99%

Regulation of human hematopoietic stem cell self-renewal by the microenvironment’s control of retinoic acid signaling

Ghiaur

Yegnasubramanian

Perkins

et al. 2013

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

121

114

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“…Retinoids-The RAR antagonist AGN194310 and the RXR agonist AGN194204 have been described previously (19,20). The RXR-specific agonists AGN195362, AGN195456, AGN195741, AGN196060, and AGN196459 and the RXR-specific antagonist AGN195393 were synthesized at Allergan.…”

Section: Methodsmentioning

confidence: 99%

Adenomatous Polyposis Coli (APC)-independent Regulation of β-Catenin Degradation via a Retinoid X Receptor-mediated Pathway

Xiao

Ghosn

Hinchman

et al. 2003

Journal of Biological Chemistry

Self Cite

138

147

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␤-catenin is a component of stable cell adherent complexes whereas its free form functions as a transcription factor that regulate genes involved in oncogenesis and metastasis. Free ␤-catenin is eliminated by two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways regulated by glycogen synthase kinase 3␤ (GSK3␤) or p53-inducible Siah-1. Dysregulation of ␤-catenin turnover consequent to mutations in critical genes of the APC-dependent pathways is implicated in cancers such as colorectal cancer. We have identified a novel retinoid X receptor (RXR)-mediated APC-independent pathway in the regulation of ␤-catenin. In this proteasomal pathway, RXR agonists induce degradation of ␤-catenin and RXR␣ and repress ␤-catenin-mediated transcription. In vivo, ␤-catenin interacts with RXR␣ in the absence of ligand, but RXR agonists enhanced the interaction. RXR agonist action was not impaired by GSK3␤ inhibitors or deletion of the GSK3␤-targeted sequence from ␤-catenin. In APC-and p53-mutated colorectal cancer cells, RXR agonists still inactivated endogenous ␤-catenin via RXR␣. Interestingly, deletion of the RXR␣ A/B region abolished ligand-induced ␤-catenin degradation but not RXR␣-mediated transactivation. RXR␣-mediated inactivation of oncogenic ␤-catenin paralleled a reduction in cell proliferation. These results suggest a potential role for RXR and its agonists in the regulation of ␤-catenin turnover and related biological events.

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“…AGN194310 (4310) was kindly provided by Rosh Chandaratna, dissolved in 95% ethanol and used at a final concentration of 100 nM (Johnson et al, 1999). BMP4 was purchased from R&D, resuspended according to the manufacturer's instructions, and added to media at a final concentration of 20 ng/ml and 2 ng/ml, respectively.…”

Section: Reagentsmentioning

confidence: 99%

Genetic deletion ofCyp26b1negatively impacts limb skeletogenesis by inhibiting chondrogenesis

Dranse

Sampaio

Petkovich

et al. 2011

Journal of Cell Science

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SummaryCyp26b1, a retinoic acid (RA)-metabolising enzyme, is expressed in the developing limb bud, and Cyp26b1 -/-mice present with severe limb defects. These malformations might be attributable to an RA-induced patterning defect; however, recent reports suggest that RA is dispensable for limb patterning. In this study, we examined the role of endogenous retinoid signalling in skeletogenesis using Cyp26b1 -/-mice and transgenic mice in which Cyp26b1 is conditionally deleted under control of the Prrx1 promoter beginning at E9.5 (Prrx1Cre + /Cyp26b1 fl/fl ). We found that the limb phenotype in Prrx1Cre + /Cyp26b1 fl/fl mice was less severe than that observed in Cyp26b1 -/-animals and that a change in retinoid signalling contributed to the difference in phenotypes. We systematically examined the role of endogenous RA signalling in chondrogenesis and found that Cyp26b1 -/-cells and limb mesenchymal cells treated with a CYP inhibitor, are maintained in a pre-chondrogenic state, exhibit reduced chondroblast differentiation and have modestly accelerated chondrocyte hypertrophy. Furthermore, Cyp26b1 -/-mesenchyme exhibited an increase in expression of genes in a closely related tendogenic lineage, indicating that retinoid signals in the limb interfere with differentiation and maintain progenitor status. Together, these findings support an important function for RA in regulating the behaviour of mesenchymal progenitors, and their subsequent differentiation and maturation.

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Synthesis and biological activity of high-affinity retinoic acid receptor antagonists

Cited by 48 publications

References 42 publications

Regulation of human hematopoietic stem cell self-renewal by the microenvironment’s control of retinoic acid signaling

Regulation of human hematopoietic stem cell self-renewal by the microenvironment’s control of retinoic acid signaling

Adenomatous Polyposis Coli (APC)-independent Regulation of β-Catenin Degradation via a Retinoid X Receptor-mediated Pathway

Genetic deletion ofCyp26b1negatively impacts limb skeletogenesis by inhibiting chondrogenesis

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