Mitogen-activated protein kinase inhibits 1,25-dihydroxyvitamin D3-dependent signal transduction by phosphorylating human retinoid X receptor α
Mitogen-activated protein kinase inhibits 1,25-dihydroxyvitamin D3-dependent signal transduction by phosphorylating human retinoid X receptor α
复制标题
DOI：
10.1172/jci6871
复制
发表时间：
1999-06-01
影响因子：
15.9
通讯作者：
Kremer, R
中科院分区：
文献类型：
--
作者：
Solomon, C;White, JH;Kremer, R
Please try later.
Human retinoid X receptor alpha (hRXR alpha) is a member of the nuclear receptor family of transcriptional regulators. It regulates transcription through its association with several heterodimeric partners, including the vitamin D-3 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 hRXR alpha 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 D-3 [1,25(OH)(2)D-3] and RXR-specific agonist LG1069 (4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naph- talenyl) ethenyl]-benzoic acid). Phosphorylation of hRXR alpha occurs at serine 260, a consensus MAP kinase site. Inhibition of MAP kinase activity or point mutagenesis of serine 260 of hRXR alpha reverses the observed resistance to 1,25(OH)(2)D-3 and LG1069. Thus, hRXR alpha is a downstream target of MAP kinase, and its phosphorylation may play an important role in malignant transformation.