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

The multidrug resistance (MDR)-associated protein, P-glycoprotein (Pgp), is expressed on the bile canalicular surface of hepatocytes, where it is thought to function in the detoxification of xenobiotics or in the transport of specific metabolites. Several studies have shown that Pgp expression in rat liver can be perturbed in vivo and in vitro; however, it is not known which of the 3 Pgp genes (class I, II, or III) are involved. In rodents, the class I and II Pgp genes have been shown to mediate MDR while the class III gene apparently does not. In this report, we have used gene-specific probes generated from the 3'-untranslated regions of the three rat Pgp genes (Deuchars et al.: Biochim. Biophys. Acta, 1130:157-165, 1992) to investigate Pgp gene expression in primary rat hepatocytes. We observed that the class II Pgp mRNA, the least abundant in the intact liver, is dramatically increased in culture over a 48 h period, while the class I Pgp showed only a modest increase in mRNA level. In contrast, the class III Pgp mRNA, which is the most abundant in the intact liver, exhibited a gradual decline. In rat liver hepatocytes, different culture conditions, as well as drugs such as cytochalasin D and colchicine, appear to affect the level of the class II Pgp gene expression. Moreover, under all these conditions, there is a strong correlation between the level of the class II Pgp and cytoskeletal (actin and tubulin) mRNAs. Thus, there may be a common mechanism regulating the expression of cytoskeletal protein genes and the class II Pgp gene. These findings have implications for our understanding of the regulation of Pgp gene expression in normal and malignant tissues.
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PMID:Differential expression of P-glycoprotein genes in primary rat hepatocyte culture. 790 Dec 27

Hyaluronan (HA) is a major glycosaminoglycan in the extracellular matrix whose expression is tightly linked to multidrug resistance and tumor progression. In this study we investigated HA-induced interaction between CD44 (a HA receptor) and Nanog (an embryonic stem cell transcription factor) in both human breast tumor cells (MCF-7 cells) and human ovarian tumor cells (SK-OV-3.ipl cells). Using a specific primer pair to amplify Nanog by reverse transcriptase-PCR, we detected the expression of Nanog transcript in both tumor cell lines. In addition, our results reveal that HA binding to these tumor cells promotes Nanog protein association with CD44 followed by Nanog activation and the expression of pluripotent stem cell regulators (e.g. Rex1 and Sox2). Nanog also forms a complex with the "signal transducer and activator of transcription protein 3" (Stat-3) in the nucleus leading to Stat-3-specific transcriptional activation and multidrug transporter, MDR1 (P-glycoprotein) gene expression. Furthermore, we observed that HA-CD44 interaction induces ankyrin (a cytoskeletal protein) binding to MDR1 resulting in the efflux of chemotherapeutic drugs (e.g. doxorubicin and paclitaxel (Taxol)) and chemoresistance in these tumor cells. Overexpression of Nanog by transfecting tumor cells with Nanog cDNA stimulates Stat-3 transcriptional activation, MDR1 overexpression, and multidrug resistance. Down regulation of Nanog signaling or ankyrin function (by transfecting tumor cells with Nanog small interfering RNA or ankyrin repeat domain cDNA) not only blocks HA/CD44-mediated tumor cell behaviors but also enhances chemosensitivity. Taken together, these findings suggest that targeting HA/CD44-mediated Nanog-Stat-3 signaling pathways and ankyrin/cytoskeleton function may represent a novel approach to overcome chemotherapy resistance in some breast and ovarian tumor cells displaying stem cell marker properties during tumor progression.
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PMID:Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. 1844 25

Microparticles (MPs) play a vital role in cell communication by facilitating the horizontal transfer of cargo between cells. Recently, we described a novel "non-genetic" mechanism for the acquisition of multidrug resistance (MDR) in cancer cells by intercellular transfer of functional P-gp, via MPs. MDR is caused by the overexpression of the efflux transporters P-glycoprotein (P-gp) and Multidrug Resistance-Associated Protein 1 (MRP1). These transporters efflux anticancer drugs from resistant cancer cells and maintain sublethal intracellular drug concentrations. By conducting MP transfer experiments, we show that MPs derived from DX breast cancer cells selectively transfer P-gp to malignant MCF-7 breast cells only, in contrast to VLB100 leukaemic cell-derived MPs that transfer P-gp and MRP1 to both malignant and non-malignant cells. The observed transfer selectivity is not the result of membrane restrictions for intercellular exchange, limitations in MP binding to recipient cells or the differential expression of the cytoskeletal protein, Ezrin. CD44 (isoform 10) was found to be selectively present on the breast cancer-derived MPs and not on leukaemic MPs and may contribute to the observed selective transfer of P-gp to malignant breast cells observed. Using the MCF-7 murine tumour xenograft model we demonstrated the stable transfer of P-gp by MPs in vivo, which was found to localize to the tumour core as early as 24 hours post MP exposure and to remain stable for at least 2 weeks. These findings demonstrate a remarkable capacity by MPs to disseminate a stable resistant trait in the absence of any selective pressure.
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PMID:Breast cancer-derived microparticles display tissue selectivity in the transfer of resistance proteins to cells. 2359 86