Nuclear receptor that identifies a novel retinoic acid response pathway

Mangelsdorf, David J.; Ong, Estelita S.; Dyck, Jacqueline A.; Evans, Ronald M.

doi:10.1038/345224a0

Cited by 1,430 publications

(712 citation statements)

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“…A CAT reporter gene containing the palindromic (inverted repeat) element TREp, which can be activated by both RARs and RXRs (47,66), was used. Figure 2A shows that as expected, RA and 9-cis RA activated transcription by both RARs and RXRs (38,44,47,66). However, SR11237 selectively activated RXRot-dependent transcription -22-fold over the control (vehicle alone) level, and RXR-y mRNAs were barely detectable in JEG-3 cells by Northern analysis (data not shown).…”

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confidence: 99%

“…Retinoid binding by RXR may further modulate the transcriptional response to T3 and vitamin D in some cases (13,39,51,65). However, regulation of gene expression by RA is more complicated because of the coexistence of two families of retinoid receptors, RA receptors (RARs) and RXRs (15,40,43,44).…”

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confidence: 99%

“…For experiments using F9 and GH3 cells, in which transfection efficiency was reduced, we used luciferase reporter plasmids (Promega) driven by the thymidine kinase promoter alone or containing either the CRBPII HRE (45) (kindly provided by M. Marks and K. Ozato) or two copies of the modified rGH HRE described above arranged as an inverted repeat (10,12) (previously referred to as 35BA; provided by D. Moore). The cDNAs for human RXRaL (44), murine RXRI (43), and murine RARa (50) subcloned into the pSG5 expression vector were used as the source of transfected receptor.…”

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Endogenous retinoid X receptors can function as hormone receptors in pituitary cells.

Davis¹,

Berrodin²,

Stelmach³

et al. 1994

Mol. Cell. Biol.

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Endogenous retinoid X receptors can function as hormone receptors in pituitary cells.

Davis¹,

Berrodin²,

Stelmach³

et al. 1994

Mol. Cell. Biol.

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“…The transcriptional effects of retinoids are mediated by their interactions with RARs (Giguere et al, 1987;Petkovich et al, 1987;Brand et al, 1988;Krust et al, 1989) and RXRs (retinoid receptors) (Mangelsdorf et al, 1990;Mangelsdorf et al, 1992) which are members of the steroid-thyroid hormone superfamily of nuclear receptors. The RARs bind all-trans-RA and its stereoisomers 9-cis-RA and 13-cis-RA (Allenby et al, 1993).…”

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Induction of the oxidative catabolism of retinoic acid in MCF-7 cells

Krekels

Verhoeven²,

Dun³

et al. 1997

Br J Cancer

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Cytochrome P450-dependent oxidation is a pathway for all-trans-retinoic acid (all-trans-RA) catabolism. Induction of this catabolic pathway was studied in MCF-7 breast cancer cells. MCF-7 cells showed low constitutive all-trans-RA catabolism. Concentration-dependent induction was obtained by preincubation of the cells with all-trans-RA (10(-9) to 10(-6) M). Onset of induction was fast, being detectable within 60 min, with maximal induction (45-fold) obtained after 16 h. Enzymatic characterization of induced all-trans-RA catabolism showed an estimated Km value (Michaelis-Menten constant) of 0.33 microM and a Vmax value (maximal velocity of an enzyme-catalysed reaction) of 54.5 fmol polar all-trans-RA metabolites 10(6) cells(-1) h(-1). These kinetic parameters represent the overall formation of polar metabolites from all-trans-RA. Induction of all-trans-RA catabolism was also obtained with other retinoids, CH55 >> 13-cis-RA = all-trans-RA > 9-cis-RA > 4-keto-all-trans-RA > 4-keto-13-cis-RA > retinol. The potency of the retinoids to induce all-trans-RA catabolism was correlated to their retinoic acid receptor affinity (Crettaz et al, 1990; Repa et al, 1990; Sani et al, 1990). Induction of all-trans-RA catabolism was inhibited by actinomycin D. Furthermore, all-trans-RA did not increase cytosolic retinoic acid-binding protein (CRABP) mRNA levels. These data suggest that induction of all-trans-RA catabolism in MCF-7 cells is a retinoic acid receptor-mediated gene transcriptional event. Induced all-trans-RA catabolism was inhibited by various retinoids with decreasing potency in the order: all-trans-RA > 4-keto-all-trans-RA > 13-cis-RA > 9-cis-RA > 4-keto-13-cis-RA > retinol > CH55. The antitumoral compound liarozole-fumarate inhibited all-trans-RA catabolism with a potency similar to that of all-trans-RA. Images Figure 4

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“…[10][11][12][13] In 1990, the family of retinoid 'X' receptors (RXRs) was described, which were shown to act as cofactors for RARs as well as receptors for vitamin D, thyroid hormone and peroxi-some proliferation-associated proteins. [14][15][16][17] Whereas all-trans RA binds only RARs, 9-cis RA binds and activates both RARs and RXRs. [18][19][20] Preclinical studies also showed that 9-cis RA was more potent than all-trans RA in inducing myeloid differentiation in HL60 cells.…”

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confidence: 99%

Clinical study of 9-cis retinoic acid (LGD1057) in acute promyelocytic leukemia

et al. 1998

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The use of all-trans retinoic acid (RA) for remission induction markedly increases survival of patients with acute promyelocytic leukemia (APL) compared to patients treated solely with cytotoxic chemotherapy. However, clinical resistance to this agent develops rapidly, which has been associated with a progressive decline in plasma drug concentrations. Previous studies suggested that 9-cis RA, a retinoid receptor 'pan agonist' did not induce its own catabolism to the same extent as alltrans RA. Therefore, we conducted a dose-ranging study of this compound in patients with both relapsed and newly diagnosed APL. We treated 18 patients with morphologically diagnosed APL (13 relapsed, five newly diagnosed). The daily dose of 9-cis RA ranged from 30 to 230 mg/m 2 /day given as a single oral dose. Four of 12 (33%) relapsed patients (three of whom were previously treated with all-trans RA) and four of five (80%) newly diagnosed patients achieved complete remission. The sole failure in the newly diagnosed group died early from an intracranial hemorrhage. One other patient with t(9;12) translocation had substantial hematologic improvement. The drug was generally well tolerated; headache and dry skin were the most common adverse reactions. Three patients were treated with corticosteroids for signs of incipient 'RA syndrome.' These preliminary data suggest that 9-cis RA is an effective agent for remission induction and deserves further investigation in patients with retinoid-sensitive APL.

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Nuclear receptor that identifies a novel retinoic acid response pathway

Cited by 1,430 publications

References 46 publications

Endogenous retinoid X receptors can function as hormone receptors in pituitary cells.

Endogenous retinoid X receptors can function as hormone receptors in pituitary cells.

Induction of the oxidative catabolism of retinoic acid in MCF-7 cells

Clinical study of 9-cis retinoic acid (LGD1057) in acute promyelocytic leukemia

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