Mitogen-activated protein kinase inhibits 1,25-dihydroxyvitamin D3–dependent signal transduction by phosphorylating human retinoid X receptor α
Autor: | Richard Kremer, Cynthia Solomon, John H. White |
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Jazyk: | angličtina |
Rok vydání: | 1999 |
Předmět: |
Keratinocytes
Tetrahydronaphthalenes Receptors Retinoic Acid Biology Retinoid X receptor Transfection Calcitriol receptor Article Calcitriol Serine Tumor Cells Cultured Animals Anticarcinogenic Agents Humans Phosphorylation Protein kinase A Cell Line Transformed MAP kinase kinase kinase Kinase General Medicine Molecular biology Cell Transformation Neoplastic Genes ras Phenotype Retinoid X Receptors Vitamin D3 Receptor Bexarotene Drug Resistance Neoplasm Mitogen-activated protein kinase COS Cells Calcium-Calmodulin-Dependent Protein Kinases biology.protein Mutagenesis Site-Directed Receptors Calcitriol Signal transduction Signal Transduction Transcription Factors |
Zdroj: | Scopus-Elsevier |
Popis: | 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. J. Clin. Invest. 103:1729–1735 (1999). |
Databáze: | OpenAIRE |
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