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) gene family has been shown to encode a membrane glycoprotein, termed the P-glycoprotein, which functions as a drug efflux pump with broad substrate specificity. This multigene family is expressed in a tissue-specific fashion in a wide variety of normal and neoplastic tissues. The regulation of mdr gene expression in normal tissues is not understood. We have recently shown that mdr mRNA and the P-glycoprotein increases dramatically in the secretory luminal and glandular epithelium of the gravid murine uterus. This observation has suggested that mdr gene expression in the uterus is controlled by the physiologic changes associated with pregnancy. This report now demonstrates that mdr mRNA and P-glycoprotein are induced at high levels in the uterine secretory epithelium by the combination of estrogen and progesterone, the major steroid hormones of pregnancy. This regulation of mdr gene expression in the uterus does not require any other contribution from the fetus or placenta. The data indicate that this gene locus is hormonally responsive to estrogen and progesterone in the uterine secretory epithelium, suggesting an important and physiologically regulated role during pregnancy.
Mol Reprod Dev 1990 Feb
PMID:Multidrug resistance gene expression is controlled by steroid hormones in the secretory epithelium of the uterus. 196 49

We report here the identification of multiple 344-bp segments of amoeba DNA similar to the human multidrug resistance (mdr) gene using primers to conserved regions of the P-glycoprotein and the polymerase chain reaction (PCR). The amino acid sequences of amoeba mdr-like PCR products were 46-97% identical to each other, 46-51% identical to human mdr1 sequences, and 30-35% identical with Plasmodium falciparum mdr-like sequences. On Northern blots, the mdr-like PCR products identified amoeba mRNAs 4.5-5 kb long, similar to the 5-kb mRNAs reported for the mammalian mdr gene. These mdr-like mRNAs were increased at least 7 times in emetine-resistant mutant clone C2 amoebae vs. wild-type clone A parasites. Furthermore, the expression of the mdr-like mRNAs was increased 3-4 times when clone C2 mutants were grown under drug pressure vs. the same parasites grown without emetine. In contrast, the number of genomic copies of the mdr-like DNA segments was not increased in the mutant clone C2 vs. the wild-type clone A amoebae, and no rearrangements of the mdr-like DNA segments by the mutant were identified on Southern blots. In conclusion, there appears to be a family of mdr-like genes in Entamoeba histolytica, which may be involved in drug resistance by the parasite because they are overexpressed in drug-resistant mutants.
Mol Biochem Parasitol 1990 Jan 15
PMID:Emetine-resistant mutants of Entamoeba histolytica overexpress mRNAs for multidrug resistance. 197 Jan 21

Hexamethylene bisacetamide (HMBA) is a potent inducer of differentiation of murine erythroleukemia cells (MELC). Commitment, the irreversible initiation of the program of terminal-cell differentiation, is first detected in HMBA-sensitive DS19-SC9 MELC in culture after 10 to 12 h of exposure to HMBA. Vincristine (VC)-resistant MELC derived from the DS19-SC9 MELC line display increased sensitivity to HMBA and become committed with little or no latent period. In the present study, we showed that the MELC line R1, which is resistant to HMBA-mediated differentiation, became sensitive to inducer if selected for a low level of VC resistance (less than 10 ng of VC per ml). Four independently derived VC-resistant cell lines from HMBA-resistant R1 cells, designated R1[VCR]a to R1[VCR]d, acquired sensitivity to HMBA and the accelerated kinetics of commitment that are characteristic of VC-resistant MELC derived from the parental DS19-SC9 cells. The calcium channel blocker verapamil suppresses the VC resistance of R1[VCR] cells but does not alter the accelerated response to HMBA. In R1[VCR] cells there was no detectable increase in the level of the 140-kilodalton P-glycoprotein. Transient inhibition of protein synthesis during the latent period delays inducer-mediated commitment of VC-sensitive DS19-SC9 MELC but does not alter the accelerated commitment kinetics of R1[VCR]a cells. Previously, we have reported evidence that protein kinase C beta (PKC beta) plays a role in HMBA-induced MELC differentiation and that compared with DS19-SC9 cells, R1 cells have a relatively low level and R1[VCR]a cells have a high level of PKC beta. These findings suggest that (i) acquisition of VC resistance overcomes the block acquired by R1 cells to HMBA-mediated differentiation; (ii) the accelerated kinetics of HMBA-induced commitment of VC-resistant MELC is not dependent on the verapamil-sensitive transport channel that is responsible, at least in part, for resistance to VC; (iii) in VC-resistant MELC, there is constitutive expression or accumulation of a protein required for HMBA-induced differentiation; and (iv) an elevated level of PKC beta activity may play a role in the altered response of R1[VCR] and other VC-resistant MELC to HMBA.
Mol Cell Biol 1990 Jul
PMID:Conversion of differentiation inducer resistance to differentiation inducer sensitivity in erythroleukemia cells. 197 44

The interaction of etoposide (VP-16), Vinca alkaloids, and verapamil with the P-glycoprotein (P-gp) was studied in human breast (MCF-7) and Chinese hamster lung (DC3F) cell lines and the corresponding multidrug-resistant MCF-7/ADR and DC3F/ADX tumor cell lines, selected for resistance to Adriamycin and actinomycin D, respectively, and overexpressing P-gp. Verapamil (10 microM) markedly reversed resistance to vincristine (11-fold in DC3F/ADX and 125-fold in MCF-7/ADR; 1-hr exposure), but it had a very modest effect on resistance to VP-16 (3- to 4-fold; 1-hr exposure). Resistant cells accumulated 2- to 4-fold less VP-16 and vincristine than the parental cell lines. Verapamil (10 microM) significantly increased accumulation and retention of vincristine, but not of VP-16, in resistant cell lines. Photoaffinity labeling of resistant cell lines with radioactive analogs of verapamil [N(p-azido-3-125I-salicyl)-N'-beta-aminoethylverapamil (NASVP)] and vinblastine[N-(p-azido-3-125I-salicyl)-N'-beta-aminoethylvindesine (NASV)] showed distinctly labeled P-gp bands in both resistant cell lines, compared with wild-type cells. Excess nonradioactive vinblastine or verapamil effectively competed with the P-gp photolabeling by either NASVP or NASV, with IC50 levels of 0.6 and 10 microM, respectively. In contrast, nonradioactive VP-16 was 100- to 500-fold less potent than vinblastine in competing with P-gp photolabeling, suggesting that VP-16 has significantly lower affinity for P-gp than Vinca alkaloids have. Taken together, our data indicate that P-gp glycoprotein by itself may not be important in the transport/efflux of VP-16 and, thus, in the mechanism of resistance to VP-16 in these cells.
Mol Pharmacol 1990 Jun
PMID:P-glycoprotein-independent mechanism of resistance to VP-16 in multidrug-resistant tumor cell lines: pharmacokinetic and photoaffinity labeling studies. 197 71

The nucleotide sequence of the mdr1 gene encoding a putative drug efflux pump (P-glycoprotein) is homologous to a class of bacterial membrane-associated transport proteins. These bacterial proteins are part of a multicomponent system that includes soluble periplasmic proteins that bind substrates, channeling them through the membrane in an energy-dependent manner. We have investigated the possibility that a similar multicomponent transport system exists in a multidrug-resistant human MCF-7 breast cancer cell line that was initially selected for resistance to doxorubicin (AdrR MCF-7). AdrR MCF-7 cells overexpress both the mdr1 gene and the pi class isozyme of glutathione S-transferase (GST-pi) (EC 2.5.1.18). The latter is one of several isozymes known to have a ligand-binding function in addition to drug-metabolizing capabilities. Although we have recently shown that transfection of a functional GST-pi expression vector is insufficient to confer resistance to doxorubicin in cells that lack P-glycoprotein expression [Mol. Pharmacol. 36:22-28 (1989)], we examined the possibility that GST-pi interacts with P-glycoprotein to alter multidrug resistance. To do this, we have cloned cDNAs encoding these proteins from AdrR MCF-7 cells, constructed expression vectors containing these two genes, and transfected these vectors sequentially into drug-sensitive MCF-7 cells. The human mdr1 cDNA isolated from AdrR MCF-7 is a variant gene whose sequence differs from that isolated previously from vinblastine-resistant KB cells [Cell 53:519-529 (1989)], resulting in an amino acid substitution of alanine to serine at position 893 (mdr1/893ala). Transfection of eukaryotic expression vectors containing the mdr1 gene isolated from AdrR MCF-7 cells produced a multidrug-resistant phenotype in recipient cells, with a cross-resistance pattern similar to that in the AdrR MCF-7 cells. To determine whether GST-pi expression could augment resistance provided by mdr1, two clones transfected with mdr1, one with high levels (153% of mdr1 RNA in AdR MCF-7 cells) and one with low levels (10% of mdr1 RNA in AdrR MCF-7 cells), were subsequently cotransfected with a GST-pi expression vector and pSVNeo and selected for resistance to G418. Six of these clones contained levels of GST-pi that were 8- to 18-fold greater than GST levels found in mdr1-expressing clones transfected with nonspecific DNA. We found no difference in the degree of resistance to doxorubicin, actinomycin D, and vinblastine between the clones expressing mdr1 only and the clones expressing both mdr1 and GST-pi.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1990 Jun
PMID:Multidrug resistance in cells transfected with human genes encoding a variant P-glycoprotein and glutathione S-transferase-pi. 197 72

Recent studies have identified two sub-families of highly conserved polypeptides in a wide variety of organisms concerned with the transport of many different compounds, specific for each transport protein. Both families, represented by HisP and HlyB, respectively, have in common a highly conserved, approximately 25 kD domain, containing an ATP-binding site. The HisP sub-family essentially consists of cytoplasmic proteins which couple energy to the import of small substrates through cytoplasmic membrane permeases in Gram-negative bacteria. The HlyB (P-glycoprotein) sub-family, on the other hand, contains a second large domain which apparently acts as the transmembrane translocator itself, which in most cases drives the secretion of a variety of compounds. These membrane domains share a number of structural features which also serve to distinguish these proteins as a closely related group. Nevertheless, the compounds secreted by the HlyB sub-family include large polypeptides, polysaccharides and a variety of anti-tumour drugs. We describe here the properties of each of these remarkable proteins and we speculate on their possible mechanism of action.
Mol Microbiol 1990 Jun
PMID:Structure and function of haemolysin B,P-glycoprotein and other members of a novel family of membrane translocators. 197 73

The pathogenic yeast, Candida albicans, is insensitive to the anti-mitotic drug, benomyl, and to the dihydrofolate reductase inhibitor, methotrexate. Genes responsible for the intrinsic drug resistance were sought by transforming Saccharomyces cerevisiae, a yeast sensitive to both drugs, with genomic C. albicans libraries and screening on benomyl or methotrexate. Restriction analysis of plasmids isolated from benomyl- and methotrexate-resistant colonies indicated that both phenotypes were encoded by the same DNA fragment. Sequence analysis showed that the fragments were nearly identical and contained a long open reading frame of 1694 bp (ORF1) and a small ORF of 446 bp (ORF2) within ORF1 on the opposite strand. By site-directed mutagenesis, it was shown that ORF1 encoded both phenotypes. The protein had no sequence similarity to any known proteins, including beta-tubulin, dihydrofolate reductase, and the P-glycoprotein of the multi-drug resistance family. The resistance gene was detected in several C. albicans strains and in C. stellatoidea by DNA hybridization and by the polymerase chain reaction.
Mol Gen Genet 1991 Jun
PMID:Analysis of a Candida albicans gene that encodes a novel mechanism for resistance to benomyl and methotrexate. 206 11

Mammalian multidrug-resistant cell lines, selected for resistance to a single cytotoxic agent, display cross-resistance to a broad spectrum of structurally and functionally unrelated compounds. These cell lines overproduce a membrane protein, the P-glycoprotein, which is encoded by a member(s) of a multigene family, termed mdr or pgp. The amino acid sequence of the P-glycoprotein predicts an energy-dependent transport protein with homology to a large superfamily of proteins which transport a wide variety of substances. This report describes the isolation and characterization of two Drosophila homologs of the mammalian mdr gene. These homologs, located in chromosomal sections 49EF and 65A, encode proteins that share over 40% amino acid identity to the human and murine mdr P-glycoproteins. Fly strains bearing disruptions in the homolog in section 49EF have been constructed and implicate this gene in conferring colchicine resistance to the organism. This work sets the foundation for the molecular and genetic analysis of mdr homologs in Drosophila melanogaster.
Mol Cell Biol 1991 Aug
PMID:Isolation and characterization of Drosophila multidrug resistance gene homologs. 207 1

We have selected and characterized Chinese hamster ovary (CHO) cells resistant to auromomycin (AUR), an antitumor antibiotic composed of a protein moiety and a nonpeptide chromophore. AUR is cytotoxic as a consequence of DNA strand-scission activity associated with the chromophore. Initial single-step selections for clones resistant to AUR detected a subpopulation of phenotypically resistant colonies, but nearly all such clones failed to display heritable resistance. One isolate that did show somewhat increased resistance was selected further and yielded a clone designated AURR-R1 that exhibits stable 10-fold increased resistance to AUR. The R1 line is also resistant to the AUR chromophore and cross-resistant to the closely related agent neocarzinostatin (NCS) and to the NCS chromophore. For AUR-treated whole cells, resistance to AUR cytotoxicity was inversely correlated with DNA damage as measured by filter elution; by contrast, isolated nuclei from sensitive and resistant cells displayed similar levels of AUR-induced DNA damage. The R1 cell line was found to be cross-resistant to colchicine, Adriamycin, Daunomycin, and vinblastine. The resistance phenotype is expressed with incomplete dominance in cell hybrids and appears similar to the "classic" multidrug resistance of CHO cells selected with other agents. Indeed, we found the multidrug-resistant CHO line CCHR-C5 to be about 5-fold cross-resistant to AUR and to NCS. We ascertained that AUR-resistant (AURR) isolates express elevated levels of the molecular weight 170,000 P-glycoprotein often associated with multidrug resistance and also contain amplified DNA sequences that contain the gene for P-glycoprotein. When multiple-step enrichment selections were carried out as an alternative approach for isolating AURR mutants, each of nine clonal isolates showed phenotypes resembling the AURR-R1 line. Thus, our findings imply that increased cellular resistance to AUR may frequently be associated with P-glycoprotein-mediated multidrug resistance.
Mol Pharmacol 1990 Aug
PMID:Characterization of auromomycin-resistant hamster cell mutants that display a multidrug resistance phenotype. 214 55

A Staphylococcus epidermidis plasmid conferring inducible resistance to 14-membered ring macrolides and type B streptogramins has been analysed and the DNA sequence of the gene responsible for resistance determined. A single open reading frame of 1.464 kbp, preceded by a complex control region containing a promoter and two ribosomal binding sites, was identified. The deduced sequence of the 488-amino-acid protein (MsrA) revealed the presence of two ATP-binding motifs homologous to those of a family of transport-related proteins from Gram-negative bacteria and eukaryotic cells, including the P-glycoprotein responsible for multidrug resistance. In MsrA, but not these other proteins, the two potential ATP-binding domains are separated by a Q-linker of exceptional length. Q-linkers comprise a class of flexible interdomain fusion junctions that are typically rich in glutamine and other hydrophilic amino acids and have a characteristic spacing of hydrophobic amino acids, as found in the MsrA sequence. Unlike the other transport-related proteins, which act in concert with one or more hydrophobic membrane proteins, MsrA appears to function independently when cloned in a heterologous host (Staphylococcus aureus RN4220). MsrA might, therefore, interact with and confer antibiotic specificity upon other transmembrane efflux complexes of staphylococcal cells. The active efflux of [14C]-erythromycin from cells of S. aureus RN4220 containing msrA has been demonstrated.
Mol Microbiol 1990 Jul
PMID:Inducible erythromycin resistance in staphylococci is encoded by a member of the ATP-binding transport super-gene family. 223 55


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