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 ATP-dependent glutathione S-conjugate export pump, named GS-X pump, has been shown to eliminate a potentially cytotoxic glutathione-platinum (GS.Pt) complex from tumor cells, thereby modulating glutathione (GSH)-associated resistance to cis-diamminedichloroplatinum(II) (cisplatin) (Ishikawa, T., and Ali-Osman, F. (1993) J. Biol. Chem. 268, 20116-20125). The present study provides evidence that the GS-X pump is functionally overexpressed in cisplatin-resistant human promyelocytic leukemia HL-60 (HL-60/R-CP) cells, in which the cellular GSH level was substantially enhanced. Indeed, the rate of ATP-dependent transport of the GS.Pt complex, measured with plasma membrane vesicles, was about 4-fold greater in HL-60/R-CP cells than in HL-60 cells. Three membrane proteins with apparent molecular masses of 200, 110, and 70 kDa were overexpressed in HL-60/R-CP cells, whereas P-glycoprotein (MDR1) was not immunologically detected in the membrane preparations from resistant and sensitive cells. Unlike in HL-60 cells, increased numbers of intracellular vesicles were observed in the cytoplasm of HL-60/R-CP cells. Fluorescence microscopy with syn-(CICH2,CH3)-1,5-diazabicyclo-[3.3.0]-octa-3,6-dione-2,8-dione (monochlorobimane) revealed that the fluorescent glutathione S-conjugate accumulated in intracellular vesicles of the cisplatin-resistant cells in an energy-dependent manner. The GS-X pump is suggested to contribute to vesicle-mediated excretion of GSH-drug conjugates from cells. In addition, both HL-60 and HL-60/R-CP cells underwent cell differentiation in response to 12-O-tetradecanoylphorbol-13-acetate, retinoic acid, and dimethyl sulfoxide, resulting in proliferation arrest as well as a remarkable decrease in the c-myc mRNA levels. After cell differentiation, a significant decrease was observed in the activity of ATP-dependent transport of the GS.Pt complex in membrane vesicles prepared from both HL-60/R-CP and HL-60 cells. These results suggest that the expression of the GS-X pump in both cisplatin-resistant and -sensitive cells is related to cell proliferation.
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PMID:GS-X pump is functionally overexpressed in cis-diamminedichloroplatinum (II)-resistant human leukemia HL-60 cells and down-regulated by cell differentiation. 796 75

Retinoic acid (RA) regulates the differentiation and proliferation of a wide variety of different cell types and all-trans RA induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL). However, clinical resistance to retinoids may develop and poses a serious problem for differentiation-inducing therapy. We studied the effects of RA in combination with a cytochrome P450 inhibitor (clotrimazole) and a P-glycoprotein antagonist (verapamil) on cell growth and differentiation of RA-resistant HL-60 cells and fresh RA-resistant leukemic cells from two APL patients. RA-resistant HL-60 cells and APL cells differentiated to mature granulocytes when cultured with all-trans RA and either clotrimazole and verapamil but not with either of the agents alone. These findings were confirmed in these cells by their increased expression of CD11b antigen and migration-inhibitory factor-related protein-8/14 mRNAs and decreased levels of c-myc mRNA. These combinations also markedly decreased the number of viable cells and inhibited cellular proliferation. After isolation of microsomes, measurements showed that levels of cytochrome P450 activities in both wild-type and RA-resistant HL-60 cells were almost comparable. Moreover, expression of the CYP1A1-type cytochrome P450 gene could not be detected in either cell type. However, RA-resistant HL-60 cells and APL cells, but not RA-sensitive HL-60 cells and APL cells, expressed multidrug-resistance-1 gene transcripts. Taken together, acquired resistance to RA may be explained in part by drug metabolism in leukemic cells. Possible mechanisms for accelerated clearance of RA include the induction of non-CYP1A1 cytochrome P450 enzymes and P-glycoprotein.
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PMID:Mechanisms of retinoid resistance in leukemic cells: possible role of cytochrome P450 and P-glycoprotein. 855 97

The human multidrug resistance gene MDR1 encodes a membrane-bound protein, referred to as P-glycoprotein, that acts as a pump to extrude toxins from cells. The 3' untranslated region (3'UTR) of the human MDR1 mRNA is very AU-rich (70%) and contains AU-rich sequences similar to those shown to confer rapid decay on c-myc, c-fos, and lymphokine mRNAs. We tested the ability of the MDR1 3'UTR to act as an mRNA destabilizing element in the human hepatoma cell line HepG2. The MDR1 mRNA has an intermediate half-life of 8 h in HepG2 cells compared to a half-life of 30 min for c-myc mRNA. The MDR1 mRNA half-life was prolonged to >20 h upon treatment with the protein synthesis inhibitor cycloheximide. We constructed expression vectors containing the human beta-globin coding region with the 3'UTR from either MDR1 or c-myc. The c-myc 3'UTR increased the decay of the chimeric mRNA, but the MDR1 3'UTR had no effect. We tested the ability of MDR1 3'UTR sequences to compete for interaction with AU-binding proteins in cell extracts; MDR1 RNA probes had a fivefold lower affinity for AU-binding proteins that interact with the c-myc AU-rich 3'UTR. Overall, our data suggest that the MDR1 3'UTR does not behave as an active destabilizing element in HepG2 cells.
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PMID:The AU-rich 3' untranslated region of human MDR1 mRNA is an inefficient mRNA destabilizer. 1044 77