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Mitogen-activated protein kinase inhibits 1,25-dihydroxyvitamin D3–dependent signal transduction by phosphorylating human retinoid X receptor α
Cynthia Solomon, … , John H. White, Richard Kremer
Cynthia Solomon, … , John H. White, Richard Kremer
Published June 15, 1999
Citation Information: J Clin Invest. 1999;103(12):1729-1735. https://doi.org/10.1172/JCI6871.
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Article

Mitogen-activated protein kinase inhibits 1,25-dihydroxyvitamin D3–dependent signal transduction by phosphorylating human retinoid X receptor α

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Abstract

Human retinoid X receptor α (hRXRα) is a member of the nuclear receptor family of transcriptional regulators. It regulates transcription through its association with several heterodimeric partners, including the vitamin D3 receptor (VDR). Signaling through the VDR is essential for normal calcium homeostasis and has been shown to inhibit the proliferation of cancer cells derived from a number of tissues. Here we show that phosphorylation of hRXRα in ras-transformed human keratinocytes through the activated Ras–Raf–mitogen-activated protein kinase (Ras-Raf-MAP kinase) pathway results in attenuated transactivation by the VDR and resistance to the growth inhibitory action of 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] and RXR-specific agonist LG1069 (4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphtalenyl) ethenyl]-benzoic acid). Phosphorylation of hRXRα occurs at serine 260, a consensus MAP kinase site. Inhibition of MAP kinase activity or point mutagenesis of serine 260 of hRXRα reverses the observed resistance to 1,25(OH)2D3 and LG1069. Thus, hRXRα is a downstream target of MAP kinase, and its phosphorylation may play an important role in malignant transformation.

Authors

Cynthia Solomon, John H. White, Richard Kremer

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Figure 5

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Effect of an RXR-specific ligand, LG1069, on HPK1A and HPK1Aras cells. (...
Effect of an RXR-specific ligand, LG1069, on HPK1A and HPK1Aras cells. (a) Cells were treated with increasing concentrations of LG1069 (10–10 to 10–6 M) in the absence or presence of 25 μM PD098059 and 5% charcoal-stripped FBS. Cell numbers were expressed as percent of DMSO vehicle-treated control cell numbers after 96 hours. Each value represents the mean ± SD of 3 determinations. Asterisks indicate a significant difference from vehicle-treated control values, whereas open circles indicate a significant difference between HPK1A and HPK1Aras cells at the LG1069 concentration indicated. (b) MTT-Microculture Tetrazolium Assay for Cell Growth (Promega Corp.). Cells were treated as in a, and formazan production was monitored by absorbance as described in Methods. Each value represents the mean ± SD of 4 determinations. Asterisks indicate a significant difference from vehicle-treated control values, whereas open circles indicate a significant difference between HPK1A and HPK1Aras cells at the LG1069 concentration indicated.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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