Identification of a functional initiator sequence in the human MDR1 promoter

Groenigen, Marjon van; Valentijn, Linda J.; Baas, Frank

doi:10.1016/0167-4781(93)90280-q

Cited by 37 publications

(16 citation statements)

References 20 publications

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“…41,42 To develop the transcriptional decoy strategy described here we took advantage of the specificity of the MDR1 gene promoter found in MDR cancer cells: this promoter is TATA-less and the choice of its transcriptional start point relies on the MED-1 cis-element located upstream 13 of the MDR1 gene initiator, 10 close to the CAAT box. The resulting configuration is unique to the human MDR1 gene as represented in Figure 7.…”

Section: Discussionmentioning

confidence: 99%

“…Both Pgp and MRP belong to the superfamily of ABC (ATP-Binding Cassette) transporters. 7,8 Regulation of the transcriptional activity of the human MDR1 gene depends on several trans-acting proteins that bind consensus cis-elements, but greatly differs from the murine homologs, in that its promoter lacks a TATA box 9 and contains an initiator element 10 at the major transcrip-sense oligodeoxynucleotide (ODN) and a 12mer doublestranded ODN, both containing the MED-1 sequence, were designed and efficiently vectorized into the nucleus with the chimerical MPG peptide. A synthetic cellular model (NIH-EGFP) and highly resistant human CEM/VLB0.…”

Section: Introductionmentioning

confidence: 99%

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Modulation of the typical multidrug resistance phenotype by targeting the MED-1 region of human MDR1 promoter

Marthinet¹,

Divita

Bernaud³

et al. 2000

Gene Ther

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Multidrug resistance of cancer (MDR) is the major cause of failure of chemotherapy. The typical MDR phenotype is due to the overexpression of membrane proteins among which the main representative is P-glycoprotein (Pgp) encoded by the MDR1 gene. Many attempts to modulate MDR by chemosensitizers have been unsuccessful in human therapy due to their intrinsic toxic effects. In an effort to modulate the MDR phenotype efficiently we designed an antisense and a transcriptional decoy strategy targeting the TATA-less human MDR1 gene promoter. The choice of the start point of transcription in a multiple start site window is related to an upstream MED-1 cis-element, the sequence and configuration of which are specific to human MDR1 gene expressed in Pgp-overproducing cancer cells. A 12mer anti-

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modulation of the typical multidrug resistance phenotype by targeting the MED-1 region of human MDR1 promoter

Marthinet¹,

Divita

Bernaud³

et al. 2000

Gene Ther

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“…The MDR1 promoter contains a heat-shock consensus element (46) and a putative xenobiotic response element that responds directly to treatment with cytotoxic agents (25,45), supporting the premise that induction of P-gp expression occurs in the presence of chemotherapeutic agents. Additionally, there is a correlation between specific point mutations in the MDR1 promoter and increased inducibility after treatment with chemotherapeutic agents (45).…”

mentioning

confidence: 96%

Doxycycline Induces Expression of P Glycoprotein in MCF-7 Breast Carcinoma Cells

Mealey¹,

Barhoumi

Burghardt

et al. 2002

Antimicrob Agents Chemother

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P-glycoprotein (P-gp) overexpression by tumor cells imparts resistance to multiple antineoplastic chemotherapeutic agents (multiple drug resistance). Treatment of tumor cells with chemotherapeutic agents such as anthracyclines, epipodophyllotoxins, andVinca alkaloids results in induction of P-gp expression. This study was performed to determine if clinically relevant antimicrobial drugs (i.e., drugs that are used to treat bacterial infections in cancer patients) other than antineoplastic agents can induce expression of P-gp in MCF-7 breast carcinoma cells. Expression of P-gp and MDR1 mRNA was determined in samples from MCF-7 cells that were treated in culture with doxorubicin (positive control) and the antimicrobial drugs doxycycline, piperacillin, and cefoperazone. The functional status of P-gp was assessed using laser cytometry to determine intracellular doxorubicin concentrations. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay was used to determine if the cytotoxicity of experimental drugs was related to their ability to induce P-gp expression. MCF-7 cells treated with doxycycline (MCF-7/doxy) were stimulated to overexpress P-gp, whereas cells treated with piperacillin and cefoperazone did not overexpress P-gp. MCF-7/doxy cells were compared to a positive-control subline, MCF-7/Adr, previously selected for doxorubicin resistance, and to MCF-7 cells treated with doxorubicin (MCF-7/doxo). All three sublines overexpressed P-gp and MDR1 mRNA and accumulated less intracellular doxorubicin than did control MCF-7 cells. P-gp expression was induced only by experimental drugs that were cytotoxic (doxorubicin and doxycycline). Doxycycline, a drug that has been used for treatment of bacterial infections in cancer patients, can induce functional P-gp expression in cancer cells, resulting in multidrug resistance.In 1970, Biedler and Riehm (3) described an in vitro model of chemotherapeutic multidrug resistance (MDR) in which cultured cells that were selected for growth in actinomycin D developed resistance to a variety of structurally and functionally diverse cytotoxic compounds. Further studies showed that the emergence of MDR was associated with increased levels of a transmembrane glycoprotein (24), P glycoprotein (P-gp). P-gp, the product of the MDR1 gene, is a 170-kDa protein that functions as an energy-dependent drug efflux pump whose substrates include naturally occurring, lipophilic agents with a complex ring structure such as Vinca alkaloids, anthracyclines, epipodophyllotoxins, and certain rhodamine dyes (18,26,37). Exposure of tumor cells to any of these substrates can generate overexpression of P-gp, resulting in the MDR phenotype.Drug exposure is thought to cause overexpression of P-gp by both selection of resistant cells and induction of P-gp expression at the level of the MDR1 promoter (14, 34). The MDR1 promoter contains a heat-shock consensus element (46) and a putative xenobiotic response element that responds directly to treatment with cytotoxic agents (25,45), supporting th...

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“…Transcription of MDR1 is regulated instead by an Inr element, first identified through in vitro studies indicating that deletion of sequences downstream of þ 5 decreased elongation of correctly initiated transcripts to undetectable levels (Cornwell, 1990). Transient transfec- tion studies then defined the sequences between À6 and þ 11 as sufficient for proper initiation of transcription in vivo Van Groenigen et al, 1993). Although Inr's have not yet been functionally described in promoters of other drug transporters, examination of the published sequences identify consensus or nearconsensus Inr's within the promoters of the MRP2 (GTACTTT) and BCRP (CCACTGC) genes (Scotto, unpublished observation).…”

Section: Constitutive (Uninduced) Transcription Of the Abc Transportersmentioning

confidence: 99%

Transcriptional regulation of ABC drug transporters

2003

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Identification of a functional initiator sequence in the human MDR1 promoter

Cited by 37 publications

References 20 publications

Modulation of the typical multidrug resistance phenotype by targeting the MED-1 region of human MDR1 promoter

Modulation of the typical multidrug resistance phenotype by targeting the MED-1 region of human MDR1 promoter

Doxycycline Induces Expression of P Glycoprotein in MCF-7 Breast Carcinoma Cells

Transcriptional regulation of ABC drug transporters

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