Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

c-Jun NH2-terminal protein kinase (JNK), a member of the mitogen-activated protein kinase family, is activated in response to many stressful stimuli including heat shock, UV irradiation, protein synthesis inhibitors, and inflammatory cytokines. In this study, we investigated whether JNK plays a role in the cellular response to different drugs commonly used in cancer chemotherapy. Treatment of human KB-3 carcinoma cells with Adriamycin resulted in a time- and dose-dependent activation of JNK of up to 40-fold. Treatment with vinblastine or etoposide (VP-16) also activated JNK, with maximum increases of 6.5- and 4.3-fold, respectively. Consistent with these findings, increased c-Jun phosphorylation was observed after drug treatment of cells. In contrast, none of the drugs significantly activated the extracellular response kinase/mitogen-activated protein kinase pathway. Since these drugs are transport substrates for the MDR1 gene product, P-glycoprotein, JNK was assayed in two multidrug-resistant (MDR) KB cell lines, KB-A1 and KB-V1, selected for resistance to Adriamycin and vinblastine, respectively. Relative to KB-3 cells, basal JNK activity was increased 7-fold in KB-A1 cells and 4-fold in KB-V1 cells, with no change in JNK protein expression, indicating that JNK is present in a more highly activated form in the MDR cell lines. Under conditions optimal for JNK activation, Adriamycin, vinblastine, and VP-16 all induced MDR1 mRNA expression in KB-3 cells. Our findings suggest that JNK activation is an important component of the cellular response to several structurally and functionally distinct anticancer drugs and may also play a role in the MDR phenotype.
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PMID:Role of the stress-activated/c-Jun NH2-terminal protein kinase pathway in the cellular response to adriamycin and other chemotherapeutic drugs. 894 82

The P-glycoprotein (Pgp) reversing agent, reserpine, induces MDR1 mRNA and PGP protein in human colon carcinoma cells (Schuetz, E. G., Beck, W. T., and Schuetz, J. D. (1996) Mol. Pharmacol. 49, 311-318) and in H35 rat hepatoma cells. Reserpine's interference with cellular dopamine utilization suggested that dopamine and dopaminergics might be important physiological regulators of PGP expression. Initial studies demonstrated that the H35 cells express the D2 dopamine receptor. Pgp protein and pgp2/mdr1b mRNA was increased (maximum of 10- and 8-fold, respectively) by the potent D2 dopamine receptor agonists bromocriptine, R(-)-propylnorapomorphine hydrochloride, and quinpirole, and Pgp protein induction was blocked by D2 receptor antagonists spiperone and clozapine. D2 receptor agonist induction of pgp2/mdr1b mRNA was paralleled by transcriptional activation of the pgp2/mdr1b promoter but blocked by pretreatment with the D2 dopamine receptor antagonists, spiperone, eticlopride, and clozapine. Co-transfection of a D2 dopamine receptor expression vector enhanced bromocriptine's transcriptional activation of the pgp2/mdr1b promoter. The G-protein, Galphai2, is required for bromocriptine transcriptional activation because the G-protein inhibitor, pertussis toxin, suppressed bromocriptine's activation of pgp2/mdr1b transcription and co-transfection of a dominant negative Galphai2 abrogated bromocriptine activation of pgp2/mdr1b. Gi proteins can transduce signals by activation of mitogen-activated protein kinases (MAPKs), and because Raf-1 is a known activator of MDR1, we tested for Raf-1 involvement. Co-transfection of a dominant negative Raf-1 failed to block bromocriptine induction of pgp2/mdr1b, and bromocriptine treatment caused no phosphorylation of the MAP kinase kinase substrates p42 and p44, demonstrating that the MAP kinase pathway was not involved. These are the first studies demonstrating transcriptional activation of an MDR gene by dopamine receptor agonists and that this activation occurs by a signal transduction pathway requiring the D2 dopamine receptor coupled to a functional G-protein.
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PMID:Bromocriptine transcriptionally activates the multidrug resistance gene (pgp2/mdr1b) by a novel pathway. 911 Oct 66

Taxol and vinblastine are widely and effectively used in the treatment of cancer, but the initial response to chemotherapy is often hampered by the development of multidrug resistant (MDR) cells. The collateral effects of these two antimitotic drugs on MDA-435 human breast carcinoma cells were investigated. When used at concentrations below those required to depolymerize microtubules, both drugs increased cyclin dependent kinase activity and stimulated the MAPK signal transduction pathway. The activity of MAPK pathway elements and cyclin dependent kinases were found to be constitutively elevated in an MDR cell line that was selected with taxol and expresses high levels of P-glycoprotein. The MDR cells maintained these alterations and also overexpressed hyperphosphorylated RB. This was manifested in a higher growth rate for MDR cells in low serum and an increased ability to form colonies in soft agar. These observations suggest that despite high levels of P-glycoprotein in MDR cells, a sufficient amount of taxol remains intracellular to accelerate the cell cycle machinery and activate the MAPK pathway. These alterations accumulate in resistant cells and contribute to a more transformed phenotype. Thus, in addition to the development of MDR, exposure of tumor cells to antimitotic agents produces further cellular changes that may contribute to the failure of chemotherapy.
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PMID:Antimitotic drugs cause increased tumorigenicity of multidrug resistant cells. 1002 81

Phosphorylation of P-glycoprotein (PGP) by some protein kinases may play an important role in the regulation of its drug transport activity, and may also be important for the development of multidrug resistance (MDR) phenotype. In the present study we investigated the expression of three groups of mitogen-activated protein kinases (MAPKs). The expression of ERKs, SAPK/JNKs and p38-MAPK was studied at the protein level in sensitive (L1210) and multidrug resistant (L1210/VCR) cells. The expression of ERKs in multidrug resistant cells did not differ from those observed in parental sensitive cells. On the other hand, the development of multidrug resistance phenotype in L1210/VCR cells was associated with increased expression of cytosolic p38-MAPK and also proteins of 90 and 130 kDa that react with antibody specific for SAPK/JNKs. The expression of the proteins mentioned was stimulated above all in conditions when vincristine was present in cultivation medium and the stimulation of transport activity of PGP was necessary for the cell survival. The development of multidrug resistance phenotype in L1210/VCR cells was not associated with significant changes in expression of several heat-shock proteins (hsp25, hsp60, hsp70, hsp90). The levels of these proteins were comparable in sensitive L1210 and resistant L1210/VCR cells, and vincristine did not influence the expression of heat-shock proteins in resistant cells.
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PMID:Differential expression of regulatory proteins in L1210/VCR cells with multidrug resistance mediated by P-glycoprotein. 1037 20

The MDR1 gene encoding the multidrug pump P-glycoprotein is transcriptionally activated in response to diverse extracellular stimuli, including the tumor promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). However, the signal transduction pathway responsible is unknown. Downstream of protein kinase C (PKC), the effects of TPA are often mediated by the Raf-1/MEK/ERK mitogen-activated protein kinase (MAPK) cascade, and Raf-1 has been implicated in MDR1 induction by serum and mitogens. Therefore, we examined the potential role of MAPK activation in TPA-mediated MDR1 induction in human leukemia K562 cells. MDR1 mRNA expression was significantly increased by TPA in the concentration range of 4 - 100 nM, with a maximal response 5 - 10 h after TPA addition. TPA-mediated MDR1 induction was inhibited by several PKC inhibitors including staurosporine, H7 and calphostin C. TPA stimulated the subcellular translocation of PKCalpha from the cytosol to the membrane and nucleus but did not affect other PKC isozymes. TPA also activated the Raf1/MEK/ERK cascade and activated another MAPK member, p38, but not JNK. In order to determine the potential role of MAPKs in MDR1 induction by TPA, specific inhibitors were utilized. The MEK inhibitor PD 098059, as well as the PKC inhibitors, completely blocked TPA-mediated ERK activation. However, under identical conditions, MDR1 induction by TPA was completely unaffected by PD 098059. Furthermore, SB 202190, which effectively inhibited TPA-mediated p38 activation, failed to inhibit TPA-induced MDR1 mRNA expression. These data demonstrate that MDR1 induction by TPA occurs via a PKC-dependent mechanism that operates independently of ERK, p38 or JNK pathways, and thus have important implications for understanding the mechanisms of MDR1 induction by extracellular stimuli.
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PMID:Phorbol ester induced MDR1 expression in K562 cells occurs independently of mitogen-activated protein kinase signaling pathways. 1052 56

In the present study, cross-drug resistance in multidrug-resistant (MDR) cells, which overexpress P-glycoprotein (Pgp), a mdr1 gene product, against Pgp-unrelated drugs, and its relevance to c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) activity were examined. The multidrug-resistant FM3A/M cells overexpressing Pgp were resistant to apoptotic cell death induced either by Pgp-related drugs including vincristine and vinblastine, which are pumped out by Pgp, or by the Pgp-unrelated drugs including 5'-fluorouracil (5-FU) and bleomycin, which are not targets for Pgp, compared with the parental FM3A cells. Verapamil reversed the resistance of FM3A/M cells to apoptosis induced by the Pgp-related drugs but not that induced by the Pgp-unrelated drugs. Interestingly, FM3A/M cells have shown significantly lower basal and drug-stimulated JNK/SAPK activities than FM3A cells. After transfection with pEBG-SEK or pEBG-SAPK constructs, FM3A/M cells recovered the basal and Pgp-unrelated drug-stimulated activities of JNK/SAPK and the susceptibility to Pgp-unrelated drug-induced apoptotic cell death comparable to those of FM3A cells. Furthermore, FM3A cells became resistant to apoptotic cell death induced by vincristine and 5-FU after transfection with pEBG-SEK(K --> R), a dominant negative inhibitory mutant of SEK. These results suggest that downregulation of JNK/SAPK activity appears to confer on Pgp-associated FM3A/M cells a cross-resistance to Pgp-unrelated drugs.
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PMID:Downregulation of JNK/SAPK activity is associated with the cross-resistance to P-glycoprotein-unrelated drugs in multidrug-resistant FM3A/M cells overexpressing P-glycoprotein. 1073 77

Intrinsic expression of the multidrug resistance (MDR) transporter P-glycoprotein (Pgp) may be regulated by reactive oxygen species (ROS). A transient expression of Pgp was observed during the growth of multicellular tumor spheroids. Maximum Pgp expression occurred in tumor spheroids with a high percentage of quiescent, Ki-67-negative cells, elevated glutathione levels, increased expression of the cyclin-dependent kinase inhibitors p27Kip1 and p21WAF-1 as well as reduced ROS levels and minor activity of the mitogen-activated kinase (MAPK) members c-Jun amino-terminal kinase (JNK), extracellular signal-regulated kinase ERK1,2, and p38 MAPK. Raising intracellular ROS by depletion of glutathione with buthionine sulfoximine (BSO) or glutamine starvation resulted in down-regulation of Pgp and p27Kip1, whereas ERK1,2 and JNK were activated. Down-regulation of Pgp was furthermore observed with low concentrations of hydrogen peroxide and epidermal growth factor, indicating that ROS may regulate Pgp expression. The down-regulation of Pgp following BSO treatment was abolished by agents interfering with receptor tyrosine kinase signaling pathways, i.e. the protein kinase C inhibitors bisindolylmaleimide I (BIM-1) and Ro-31-8220, the p21ras farnesyl protein transferase inhibitor III, the c-Raf inhibitor ZM 336372 and PD98059, which inhibits ERK1,2 activation. ROS involved as second messengers in receptor tyrosine kinase signaling pathways may act as negative regulators of Pgp expression.
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PMID:Down-regulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by reactive oxygen species. 1127 18

Metals, such as arsenic or cadmium, have recently been demonstrated to interact with metabolic pathways, including phase I and phase II enzymes and the phase III efflux pump P-glycoprotein. In the present study, we investigated the effects of heavy metals and metalloids on the expression of the multidrug resistance-associated protein 2 (MRP2), a major hepatic transporter. Treatment of primary rat hepatocytes by sodium arsenite [As(III)], sodium arsenate and potassium antimony tartrate, but not cadmium chloride, was shown to markedly increase MRP2 mRNA and protein levels; As(III)-mediated induction was dose- and time-dependent and paralleled a strong increase in MRP2 amounts as assessed by Western blotting. As(III) was also demonstrated to markedly up-regulate MRP2 gene expression in primary human hepatocytes. MRP2 mRNA induction occurring in As(III)-treated rat hepatocytes was fully blocked by actinomycin D, indicating that it required active gene transcription. It was associated with an activation of the c-Jun N-terminal kinase pathway and with a reduction of cellular glutathione levels. Quercetin, a flavonoid compound known to block As(III)-related induction of P-glycoprotein, was also found to prevent up-regulation of MRP2 gene expression in rat hepatocytes exposed to As(III). Such an effect was unlikely to be due to alteration of JNK pathway since quercetin failed to abolish As(III)-induced JNK phosphorylation. It may rather be linked to the increase of cellular glutathione levels by quercetin, thus limiting the depleting effects of As(III) on glutathione amounts. Finally, these results confirm that some metals strongly regulate expression of detoxifying proteins, including biliary drug transporters.
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PMID:Arsenic induces expression of the multidrug resistance-associated protein 2 (MRP2) gene in primary rat and human hepatocytes. 1140 47

P-glycoprotein (P-gp) is the plasma membrane transport pump responsible for efflux of chemotherapeutic agents from cells and is one of the systems that secures multidrug resistance (MDR) of neoplastic cells. In the present study, drug sensitive L1210 and multidrug resistant L1210/VCR (characterized by overexpression of P-gp) mouse leukemic cell lines were used as an experimental model. We have found that SB203580, a specific inhibitor of p38-MAPK pathway, significantly reduced the degree of the vincristine resistance in L1210/VCR cells. This phenomenon was accompanied by a decrease in the LC(50) value of vincristine from 3.203+/-0.521 to 0.557+/-0.082 microM. The LC(50) value of sensitive cells for vincristine was about 0.011 microM. The effect of SB203580 on L1210/VCR cells was associated with significantly increased intracellular accumulation of [3H]-vincristine in the concentration dependent manner. Prolonged exposure of resistant cells to 30 microM SB203580 did neither significantly influence the gene expression of P-gp, nor change the protein levels of p38-MAPK. Western blot analysis revealed that the MDR phenotype in L1210/VCR cells was associated with increased level and activity of cytosolic p38-MAPK. In resistant cells, the enhanced phosphorylation of both, p38-MAPK and ATF-2 (endogenous substrate for p38-MAPK) was found as well. In conclusion we could remark that SB203580, an inhibitor of p38 kinase pathway, reversed the MDR resistance of L1210/VCR cells. MDR phenotype of these cells is connected with increased levels and activities of p38-MAPK. These findings point to the possible involvement of the p38-MAPK pathway in the modulation of P-gp mediated multidrug resistance in the L1210/VCR mouse leukemic cell line. However, the mechanisms of SB203580 action should be further investigated.
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PMID:SB203580, a specific inhibitor of p38-MAPK pathway, is a new reversal agent of P-glycoprotein-mediated multidrug resistance. 1145 47

Resistance to multiple, unrelated cancer chemotherapeutic drugs can be mediated by P-glycoprotein, the MDR1 gene product. Numerous substances, including chemotherapeutic drugs, heavy metals, growth factors, activated oncogenes, or changes in temperature increase MDR1 gene expression. Because several of these factors regulate cellular function through the activation of phospholipase C (PLC), we postulated that PLC-mediated signaling could be central to regulating the expression of MDR1. Transfection of NIH 3T3 cells with a pMJ30-PLC-gamma 1 expression vector increased the activity of the MDR1 promoter by 2- to 10-fold. PLC-mediated activation required a region between -106 and -99 of the MDR1 promoter. Treatment of cotransfected cells with platelet-derived growth factor further enhanced the activity of the MDR1 promoter. The stimulatory effect of PLC on the MDR1 promoter was increased by cotransfection with constitutively active v-raf and was blocked by the dominant-negative mutant, c-Raf-C4. The activity of mitogen-activated protein kinase (MAPK) was also increased in PLC-gamma 1-transfected cells. Furthermore, PD-98059 and U0126, two MAPK inhibitors, blocked PLC-gamma 1-induced expression of MDR1. The results of Northern blot analysis showed that activation of PLC by heat shock and growth factors increased expression of endogenous MDR1 mRNA in human renal carcinoma cells. These effects were blocked by inhibitors of the PLC-MAPK pathway. In summary, our results indicate for the first time that activation of PLC by a variety of cellular stimuli can regulate the expression of MDR1 and that the transcriptional modulation of MDR1 expression by PLC is mediated by the Raf-MAPK pathway.
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PMID:Activation of phospholipase C induces the expression of the multidrug resistance (MDR1) gene through the Raf-MAPK pathway. 1156 28


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