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)

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

P-glycoprotein (P-gp)/multi-drug resistance 1 (MDR1) gene is recognized to be, at least in part, responsible for the refractoriness to chemotherapy of leukemia. The transcriptional mechanism of MDR1 gene is largely unknown. However, recent reports have clarified that early growth response 1 gene (Egr1) positively regulates MDR1 transcription, while Wilms' tumor suppressor gene (WT1) does negative regulation of MDR1 gene expression in 12-O-tetradecanoylphorbol-13-acetate treated K562 cells. In addition, Egr1 and WT1 are structurally related transcription factors and bind to quite similar DNA sequences. Our study of mRNA expression profile of Egr1, WT1 and MDR1 in fresh AML samples demonstrated that there are disease-specific patterns. Egr1 mRNA was frequently and strongly expressed in monocytic leukemia cells, especially in AML M4 cells. WT1 mRNA was undetectable in t(8;21) AML cells. mRNA expression of MDR1 was frequent in AML M1 and t(8;21) AML cells, in which the expression level was highest in AML M1 and was low in monocytic leukemia (M4 and M5). Then, expression level of MDR1 was inversely correlated with Egr1. By liquid culture of leukemia cell lines and fresh AML cells with the addition of all-trans retinoic acid (ATRA), modulation of P-gp/MDR1 and Egr1 was observed and the pattern of modulation was divided into four groups: (1) blastic AML type, in which distinct expression of P-gp/MDR1 and CD34 was not influenced by ATRA; (2) t(8;21)AML type, in which P-gp/MDR1 expression was augmented by ATRA, while CD34 was kept high; (3) AML M3 type, in which P-gp/MDR1 expression was reduced with granulocytic differentiation by ATRA; (4) monocytic AML type, in which P-gp/MDR1 expression was augmented by ATRA, while CD34 expression decreased, and strong Egr1 expression was downregulated just prior to the augmentation of P-gp/MDR1 expression. WT1 expression was not influenced by the addition of ATRA in each group. Previous reports have suggested that P-gp/MDR1 plays an important role in resistance to chemotherapy, and is recognized as one of the stem cell marker. However, P-gp/MDR1 expression augmented by ATRA, which was observed in monocytic AML, was recognized as a functional molecule of mature monocyte/macrophage, because CD34 expression decreased and CD13 expression increased by ATRA. Finally, expression of P-gp/MDR1 in monocytic leukemia, which was functionally confirmed by Rh123 efflux study, was thought to be closely related to the characteristic modulation of Egr1 expression by ATRA.
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PMID:Augmented expression of P-gp/multi-drug resistance gene by all-trans retinoic acid in monocytic leukemic cells. 1173 1

We have shown that inhibition of WT1/+17AA protein expression following transfection with a vector-based small interfering RNA expression construct in K562 cell lines, leads to a decrease in MDR1 and P-glycoprotein levels, accumulation of Rh123, and enhancement of the doxorubicin cytotoxicity. Our findings suggest that WT1/+17AA exerts its oncogenic function by modulating multidrug resistance in leukemia cells.
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PMID:Down-regulation of WT1/+17AA gene expression using RNAi and modulating leukemia cell chemotherapy resistance. 1776 25

There are several important biological markers in myeloid leukemia. In particular, WT1, FLT3, P-glycoprotein (P-gp) and surface antigens are important biologic markers. When we monitor the treatment of leukemia, WT1 is considered to be an important marker, and has been applied to immune therapy. The abnormality of the genes of FLT3 and expression of P-gp are poor prognostic factors, and their inhibitors are developed in progress. The surface antigen analysis of blast cells is also used in the classification and the treatment strategy decision. Recently, as for the treatment of leukemia, stratification by various kinds of factors has been adopted in many prospective studies. The results of these biological markers are utilized for the stratification.
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PMID:[Biological markers for diagnosis of myeloid leukemia]. 1986 Jan 90