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The Journal of biological chemistry v.292 no.4, 2017년, pp.1490 - 1509   SCI SCIE
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Phosphorylation of Human Retinoid X Receptor α at Serine 260 Impairs Its Subcellular Localization, Receptor Interaction, Nuclear Mobility, and 1α,25-Dihydroxyvitamin D3-dependent DNA Binding in Ras-transformed Keratinocytes

Jusu, Sylvester (From the Department of Medicine, Calcium Research Laboratory, Royal Victoria Hospital, McGill University, Montreal, Quebec H4A 3J1, ) ; Presley, John F. (the Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 0C7, and ) ; Kremer, Richard (From the Department of Medicine, Calcium Research Laboratory, Royal Victoria Hospital, McGill University, Montreal, Quebec H4A 3J1, ) ;
  • 초록  

    Human retinoid X receptor α (hRXRα) plays a critical role in DNA binding and transcriptional activity through heterodimeric association with several members of the nuclear receptor superfamily, including the human vitamin D receptor (hVDR). We previously showed that hRXRα phosphorylation at serine 260 through the Ras-Raf-MAPK ERK1/2 activation is responsible for resistance to the growth inhibitory effects of 1α,25-dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 ), the biologically active metabolite of vitamin D 3 . To further investigate the mechanism of this resistance, we studied intranuclear dynamics of hVDR and hRXRα-tagged constructs in living cells together with endogenous and tagged protein in fixed cells. We find that hVDR-, hRXRα-, and hVDR-hRXRα complex accumulate in the nucleus in 1α,25(OH) 2 D 3 -treated HPK1A cells but to a lesser extent in HPK1ARas-treated cells. Also, by using fluorescence resonance energy transfer (FRET), we demonstrate increased interaction of the hVDR-hRXRα complex in 1α,25(OH) 2 D 3 -treated HPK1A but not HPK1ARas cells. In HPK1ARas cells, 1α,25(OH) 2 D 3 -induced nuclear localization and interaction of hRXRα are restored when cells are treated with the MEK1/2 inhibitor UO126 or following transfection of the non-phosphorylatable hRXRα Ala-260 mutant. Finally, we demonstrate using fluorescence loss in photobleaching and quantitative co-localization with chromatin that RXR immobilization and co-localization with chromatin are significantly increased in 1α,25(OH) 2 D 3 -treated HPK1ARas cells transfected with the non-phosphorylatable hRXRα Ala-260 mutant. This suggests that hRXRα phosphorylation significantly disrupts its nuclear localization, interaction with VDR, intra-nuclear trafficking, and binding to chromatin of the hVDR-hRXR complex.


  • 주제어

    fluorescence resonance energy transfer (FRET) .   mitogen-activated protein kinase (MAPK) .   phosphorylation .   retinoid .   vitamin D .   fluorescence loss in photobleaching (FLIP) .   retinoid X receptor .   vitamin D receptor.  

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