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12-O-tetradecanoylphorbol-13-acetate activation of the MDR1 promoter is mediated by EGR1. 总被引:5,自引:0,他引:5
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P-glycoprotein, the product of the MDR1 gene (multidrug resistance gene 1), is an energy-dependent efflux pump associated with treatment failure in some hematopoietic malignancies. Its expression is regulated during normal hematopoietic differentiation, although its function in normal hematopoietic cells is unknown. To identify cellular factors that regulate the expression of MDR1 in hematopoietic cells, we characterized the cis- and trans-acting factors mediating 12-O-tetradecanoylphorbol-13-acetate (TPA) activation of the MDR1 promoter in K562 cells. Transient-transfection assays demonstrated that an MDR1 promoter construct containing nucleotides -69 to +20 conferred a TPA response equal to that of a construct containing nucleotides -434 to +105. TPA induced EGR1 binding to the -69/+20 promoter sequences over a time course which correlated with increased MDR1 promoter activity and increased steady-state MDR1 RNA levels. The -69/+20 promoter region contains an overlapping SP1/EGR site. The TPA-responsive element was localized to the overlapping SP1/EGR site by using a synthetic reporter construct. A mutation in this site that inhibited EGR protein binding blocked the -69/+20 MDR1 promoter response to TPA. The expression of a dominant negative EGR protein also blocked the TPA response of the -69/+20 promoter construct. Finally, the expression of EGR1 was sufficient to activate a construct containing tandem MDR1 promoter SP1/EGR sites. These data suggest a role for EGR1 in modulating MDR1 promoter activity in hematopoietic cells. 相似文献
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Singh IS Viscardi RM Kalvakolanu I Calderwood S Hasday JD 《The Journal of biological chemistry》2000,275(13):9841-9848
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The possible role of heat shock factor-1 in the negative regulation of heme oxygenase-1 总被引:1,自引:0,他引:1
Chou YH Ho FM Liu DZ Lin SY Tsai LH Chen CH Ho YS Hung LF Liang YC 《The international journal of biochemistry & cell biology》2005,37(3):604-615
We examined a possible role for heat shock factor-1 (HSF-1) in the negative regulation of HO-1 gene expression in human Hep3B hepatoma cells responding to stimulation with 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) and arsenite. Overexpression of HSF-1 and heat-shock experiments indicated that HSF-1 repressed the 15d-PGJ2-and arsenite-induced HO-1 gene expression through directly binding to the consensus heat shock element (HSE) of the HO-1 gene promoter. In addition, point mutations at specific HSE sequences of the HO-1 promoter-driven luciferase plasmid (pGL2/hHO3.2-Luc) abolished the heat shock- and HSF-1-mediated repression of reporter activity. Overall, it is possible that HSF-1 negatively regulates HO-1 gene expression, and that the HSE present in the -389 to -362 region mediates HSF-1-induced repression of human HO-1 gene expression. 相似文献
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