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)

One reason for the failure of chemotherapy is the overexpression of the multidrug resistance gene, MDR1. The product of this gene is the multidrug transporter P-glycoprotein, an ATP-dependent pump that extrudes drugs from the cytoplasm. Some tumors inherently express P-glycoprotein, whereas others acquire the ability to do so after exposure to certain chemotherapeutic agents, often by the mechanism of gene amplification. Classical Wilms' tumors (nephroblastoma) typically respond to therapy and have a good prognosis. On the contrary, anaplastic Wilms' tumors are generally refractory to chemotherapy. These anaplastic variants are rare (4.5% of all Wilms' tumors reported in the United States), aggressive, and often fatal forms of tumor, which are commonly thought to result from the progression of classical Wilms' tumors. To investigate the basis for this differential response to therapy, we examined a number of classical and anaplastic Wilms' tumors for the expression of the MDR1 gene by immunohistochemical and mRNA analysis. Classical Wilms' tumors consistently did not express P-glycoprotein except in areas of tubular differentiation, as in normal kidney. Similarly, two of three anaplastic tumors failed to show P-glycoprotein expression. In contrast, cultured cells derived from a third anaplastic tumor, W4, exhibited strong P-glycoprotein expression and were drug resistant in vitro. Southern analysis revealed that W4 cells contained a single copy of the MDR1 gene per haploid genome similar to normal cells, demonstrating that the overexpression of MDR1 was not caused by gene amplification. Transcriptional activation of the MDR1 gene would be in keeping with the concept that p53 might act as a transcriptional repressor of the MDR1 gene.
 ...
PMID:Anaplasia and drug selection-independent overexpression of the multidrug resistance gene, MDR1, in Wilms' tumor. 912 18

Selective inhibition of the multidrug resistance 1 (MDR1) gene and its product, the P-glycoprotein, a membrane transporter responsible for multidrug resistance, could be an important approach for enhancing cancer therapeutics. An emerging strategy for selective gene regulation involves designed zinc finger proteins that can recognize specific sequences in the promoter regions of disease-related genes. Herein, we investigate the behavior of clones of multidrug-resistant NCI/ADR-RES breast carcinoma cells displaying ponasterone-inducible expression of a designed transcriptional repressor targeted to the MDR1 promoter. The controlled production of this novel repressor resulted in major reductions in P-glycoprotein levels in these otherwise highly drug-resistant tumor cells. The regulated reduction of MDR1 expression in NCI/ADR-RES cells was accompanied by a marked increase in the rate of uptake of the P-glycoprotein substrate rhodamine 123. In addition, the cytotoxicity profile of the antitumor drug doxorubicin was dramatically altered in the induced cells compared with controls. The expression levels of other genes were examined both by a DNA array analysis of approximately 2000 genes and by biochemical techniques. Although some changes were observed in mRNA levels of nontargeted genes, the most dramatic effect by far was on MDR1, indicating that the action of the designed transcriptional repressor was quite selective. This study suggests that designed transcriptional regulators can be used to strongly and selectively influence expression of cancer-related genes, even under circumstances of extensive amplification of the target gene.
 ...
PMID:Selective inhibition of P-glycoprotein expression in multidrug-resistant tumor cells by a designed transcriptional regulator. 1218 53

The t(12;21)(p12;q22) chromosomal aberration, which is frequently observed in pediatric precursor B-cell acute lymphoblastic leukemia (ALL), generates the TEL/AML1 chimeric gene and protein. TEL/AML1-positive ALL has a favorable prognosis, and one possible reason is that this subtype of ALL rarely shows drug resistance. AML1/ETO, another AML1-containing chimeric protein, has been shown to transcriptionally repress the activity of the multidrug resistance-1 (MDR-1) gene promoter; thus, we examined whether TEL/AML1 also represses MDR-1 gene expression, possibly preventing the emergence of multidrug resistance. In this study, we show that the TEL/AML1 protein binds to the consensus AML1 binding site in the MDR-1 promoter and transcriptionally represses its activity. Following transient transfection of TEL/AML1 protein into Adriamycin-resistant K562/Adr cells, we also demonstrate that TEL/AML1 can down-regulate the expression of P-glycoprotein, a product of the MDR-1 gene, and restore the chemosensitivity to the cells. Furthermore, we report that MDR-1 mRNA levels in leukemic cells obtained from TEL/AML1-positive ALL patients are lower than those from TEL/AML1-negative ALL patients. Thus, TEL/AML1 protein acts as a transcriptional repressor of MDR-1 gene expression, and although TEL/AML1 has been implicated in leukemogenesis, its effects on the MDR-1 gene may contribute to the excellent prognosis of TEL/AML1-positive ALL with current therapy.
 ...
PMID:TEL/AML1 overcomes drug resistance through transcriptional repression of multidrug resistance-1 gene expression. 1523 9