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)

The expression of mdr genes that encode P-glycoprotein, an integral membrane drug transporter, has been associated with the emergence of the multidrug resistance phenotype during treatment with cancer chemotherapeutic drugs. To understand the regulation of the mdr genes, the murine mdr1b promoter has been isolated and characterized in our laboratory. Three nuclear protein binding sites that interact with nuclear proteins present in both drug-sensitive and -resistant murine macrophage-like 1774.2 cells have been localized to the promoter. In this report, transcription factor NF-Y has been identified as binding to the Y-box sequence in site 1 and as a major factor in the regulation of the murine mdr1b promoter in the mouse adrenal cell line, Y-1, that endogenously expresses the mdr1b gene. The expression of CCAAT/enhancer binding protein beta (C/EBP beta) in Y-1 cells augmented mdr1b promoter activity and resulted in an increased level of mdr1b mRNA. The effect of C/EBP beta expression on mdr1b promoter activity was sensitive to mutations in the Y-box, suggesting that coordination of NF-Y with C/EBP beta is required for further activation of the mdr1b promoter. Our studies have indicated that NF-Y is a critical factor for the mdr1b promoter, and its coordination with other factors, such as C/EBP beta, could be an important mechanism involved in mdr1b gene expression.
 ...
PMID:Coordination of transcription factors, NF-Y and C/EBP beta, in the regulation of the mdr1b promoter. 901 55

Previously, we showed that the nuclear factor NF-IL6 binds and trans-activates the promoter of the human multidrug resistance gene (MDR1) encoding P-glycoprotein (N. J. Combates et al., J. Biol. Chem., 269: 29715-29719, 1994). In this study, we investigated the physiological relevance of MDR1 gene regulation by NF-IL6 in response to PMA (phorbol 12-myristate 13-acetate)-induced differentiation. Treatment of U937 cells, a human promonocytic cell line, with PMA induced their differentiation along the macrophage/monocytic cell lineage. The cellular changes were found to be accompanied by an increase in P-glycoprotein expression at the cell surface. PMA treatment of U937 cells also resulted in the synthesis of the three forms of NF-IL6 and an enhanced DNA binding activity of nuclear extracts to a probe derived from the MDR1 promoter. The majority of the DNA-protein complex could be supershifted by an NF-IL6 reactive antibody but not by antibodies for CAAT/enhancer binding protein alpha and delta, c-fos, or c-jun. Furthermore, transient transfection studies demonstrated that PMA enhanced the activity of a MDR1 promoter-driven luciferase gene construct to a greater extent as compared with the activity of a reporter construct containing mutations within the NF-IL6 responsive element. These results indicate a correlation between NF-IL6 gene expression and the regulation of the MDR1 gene. Furthermore, these observations also suggest that P-glycoprotein expression is part of the macrophage differentiation process.
 ...
PMID:Involvement of the transcription factor NF-IL6 in phorbol ester induction of P-glycoprotein in U937 cells. 904 Sep 43

Multidrug resistance, the phenomenon by which cells treated with a drug become resistant to the cytotoxic effect of a variety of other structurally and functionally unrelated drugs, is often associated with the expression of P-glycoprotein, an efflux membrane pump coded by the MDR1 (ABCB1) gene. Transcription from MDR1 can start at 2 promoters: a well-characterized downstream promoter and an as yet uncharacterized upstream promoter (USP). We have previously determined that the USP is activated in some drug-resistant cell lines, in primary breast tumors and in metastatic epithelial cells isolated from the lymph nodes of breast cancer patients. In this study, we report the cloning and characterization of the MDR1 USP and studied its association with chemotherapy response in breast cancer patients. Deletion analysis indicated that a nearby endogenous retroviral long terminal repeat is not responsible for promoter activation, and that the region within the first 400 nucleotides upstream from the transcription start point contained all the elements necessary for promoter activity in drug-resistant cells. We identified an element recognized by the transcription factor NF-IL6 (activated upon interleukin-6 exposure) which is necessary for promoter activity in drug-resistant cells and plays a role in the activation of the promoter in response to interleukin-6 in breast cancer MCF-7 cells. Although transcripts from this promoter are associated with translating polyribosomes, their low abundance makes the amount of synthesized P-glycoprotein insufficient to affect the response to first-line chemotherapy in patients with advanced breast cancer.
 ...
PMID:Production of P-glycoprotein from the MDR1 upstream promoter is insufficient to affect the response to first-line chemotherapy in advanced breast cancer. 1795 90