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

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 1

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Effect of 1,25(OH)2D3 and PD098059 on cell growth in HPK1A and HPK1Aras ...
Effect of 1,25(OH)2D3 and PD098059 on cell growth in HPK1A and HPK1Aras cells. Cells were transfected with the mOP3 reporter plasmid (20) and the growth hormone expression plasmid pLTR-GH, and then were treated with increasing concentrations of 1,25(OH)2D3 and 5% charcoal-stripped FBS in the absence or presence of 25 μM PD098059. (a) CAT activity was assayed after 24 hours and normalized for transfection efficiency by the corresponding hGH activity. (b) Cells were treated as above, and cell numbers were expressed as percent of vehicle-treated control cell numbers after 96 hours. Each value represents the mean ± SD of 3 determinations and is representative of 3 different experiments. Asterisks indicate a significant difference from vehicle-treated control values, whereas open circles indicate a significant difference between HPK1A and HPK1Aras cells in the absence of PD098059 at the 1,25(OH)2D3 concentration indicated.