Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:12-O-tetradecanoylphorbol-13-acetate activation of the MDR1 promoter is mediated by EGR1. 756 62

Overexpression of P-glycoprotein, the product of the multidrug resistance-1 (MDR1) gene, is associated with treatment failure in some hematopoietic tumors. Although expression of P-glycoprotein in normal hematopoietic cells is tightly regulated during hematopoietic differentiation, its aberrant overexpression in hematopoietic malignancies occurs at the transcriptional level. We have demonstrated that 12-O-tetradecanoylphorbol-13-acetate (TPA) increases transcription of the MDR1 gene and activates the MDR1 promoter, and that promoter activation by TPA requires binding of the zinc finger transcription factor EGR1 to specific MDR1 promoter sequences (C. McCoy and M. M. Cornwell, Mol. Cell. Biol., 15: 6100-6108, 1995). We demonstrate here that the Wilms' tumor (WT) suppressor, WT1, a member of the EGR family, inhibits the response of the MDR1 promoter to TPA in K562 cells. Inhibition is likely a direct effect of WT1 binding to the MDR1 promoter because: (a) WT1 expression does not inhibit the increase in EGR1 after TPA treatment; (b) inhibition by WT1 requires the zinc finger domain; (c) WT1 binds to MDR1 promoter sequences that bind EGR1 and are responsive to TPA; and (d) there is an inverse correlation between WT1 protein expression and MDR1 expression and promoter activity. These results suggest that the MDR1 gene is a target for regulation by WT1 and suggest mechanisms by which MDR1 may be regulated by WT1 and EGR1 during normal and aberrant hematopoiesis.
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PMID:The Wilms' tumor suppressor, WT1, inhibits 12-O-tetradecanoylphorbol-13-acetate activation of the multidrug resistance-1 promoter. 1039 99

The ability to selectively regulate the expression of genes implicated in cancer or other diseases could have important ramifications for both basic research and for therapy. Using peptide combinatorial libraries expressed in yeast, we have screened for novel zinc finger proteins that selectively bind to an overlapping EGR1/SP1/WT1 regulatory site in the promoter of the MDR1 multidrug resistance gene. The novel proteins were only moderately effective in blocking transcription by simple masking of the target site. However, when coupled to mammalian transactivator or repressor domains, they could selectively modulate the expression of reporter genes having promoters containing the MDR1 target site. Moreover, they could also regulate transcription of the chromosomal MDR1 gene. Thus, in K562 cells, 12-O-tetradecanoylphorbol-13-acetate-inducible expression of P-glycoprotein, the product of MDR1 gene, was strongly and selectively inhibited by the presence of a repressor protein targeted to the MDR1 promoter. These studies potentially provide a novel alternative approach to the control of multidrug resistance. They also provide important insights into strategies for developing selective regulators of gene expression.
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PMID:Regulation of the MDR1 gene by transcriptional repressors selected using peptide combinatorial libraries. 1086 Sep 21