Transcriptional regulators of the human multidrug resistance 1 gene: recent views

Labialle, Stéphane; Gayet, Landry; Marthinet, Eric; Rigal, Dominique; Baggetto, Loïc

doi:10.1016/s0006-2952(02)01156-5

Cited by 158 publications

(90 citation statements)

References 54 publications

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“…Transcriptional activation is generally accepted to be the principle mechanism for up-regulating MDR1 gene expression (Labialle et al, 2002). Several regulatory elements such as Sp1, AP-1, NF-Y, and C/EBPβ, have been characterized.…”

Section: Discussionmentioning

confidence: 99%

Depletion of mitochondrial DNA up-regulates the expression of MDR1 gene via an increase in mRNA stability

et al. 2008

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The mutation and reduction of mitochondrial DNA (mtDNA) have been suggested as factors in the carcinogenesis. However, whether the depletion of mtDNA induces multidrug resistance in cancer cells has not been fully investigated. To elucidate the association of cellular mtDNA content and drug resistance, we generated HCT-8 colon cancer cells which revealed a marked decrease in cellular mtDNA and ATP content, concomitant with a lack of mRNAs encoded by mtDNA. The mtDNA-depleted cells showed a decreased sensitivity and accumulation of anti-cancer drugs, suggesting that mtDNA depletion could develop multidrug resistance (MDR) phenotype in HCT-8 cells. We found that the expression level of MDR1 mRNA and its translated product P-glycoprotein was increased in the mtDNA-depleted cells, indicating that the decrease of sensitivity and accumulation of anti-cancer drug in the mtDNA-depleted cells might be due to a substantial increase in the expression of P-glycoprotein. Furthermore, increased expression of MDR1 mRNA and P-glycoprotein was due to an increase of mRNA stability rather than transcriptional activation. Taken together, these results indicate that mtDNA depletion can induce an increased P-glycoprotein expression via an increase of mRNA stability and suggest that the mtDNA depletion in cancer cells plays an important role in the induction of MDR phenotype.

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Section: Discussionmentioning

confidence: 99%

Depletion of mitochondrial DNA up-regulates the expression of MDR1 gene via an increase in mRNA stability

et al. 2008

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“…Epigenetic mechanisms (histone acetylation, DNA methylation) have been shown to play a pivotal role in ABCB1 gene expression in several tumour cell systems (El-Osta et al, 2002;Labialle et al, 2002;Scotto, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Considerable progress has been made towards the definition of the regulatory mechanisms that control the expression of ABCB1 gene in tumour cells (for review, see Labialle et al, 2002;Scotto, 2003). The ABCB1 promoter lacks a TATA box and contains an initiator element (Inr) necessary for its transcription.…”

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confidence: 99%

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

et al. 2007

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Tumour drug-resistant ABCB1 gene expression is regulated at the chromatin level through epigenetic mechanisms. We examined the effects of the histone deacetylase inhibitor trichostatin A (TSA) on ABCB1 gene expression in small cell lung carcinoma (SCLC) drugsensitive (H69WT) or etoposide-resistant (H69VP) cells. We found that TSA induced an increase in ABCB1 expression in drugsensitive cells, but strongly decreased it in drug-resistant cells. These up-and downregulations occurred at the transcriptional level. Protein synthesis inhibition reduced these modulations, but did not completely suppress them. Differential temporal patterns of histone acetylation were observed at the ABCB1 promoter: increase in H4 acetylation in both cell lines, but different H3 acetylation with a progressive increase in H69WT cells but a transient one in H69VP cells. ABCB1 regulations were not related with the methylation status of the promoter À50GC, À110GC, and Inr sites, and did not result in further changes to these methylation profiles. Trichostatin A treatment did not modify MBD1 binding to the ABCB1 promoter and similarly increased PCAF binding in both H69 cell lines. Our results suggest that in H69 drug-resistant SCLC cell line TSA induces downregulation of ABCB1 expression through a transcriptional mechanism, independently of promoter methylation, and MBD1 or PCAF recruitment.

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“…Transcriptional regulation of the ATP binding cassette (ABC) transporter genes plays a pivotal role in the development of a drug resistance phenotype in mammalian (1,2) and yeast cells (3)(4)(5). Constitutive transcriptional up-regulation of drug transporter genes occurs in certain mutations involving various transcriptional activators.…”

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confidence: 99%

On the Mechanism of Constitutive Pdr1 Activator-mediated PDR5 Transcription in Saccharomyces cerevisiae

Gao

Wang

Milgröm

et al. 2004

Journal of Biological Chemistry

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Drug resistance as a result of overexpression of drug transporter genes presents a major obstacle in the treatment of cancers and infections. The molecular mechanisms underlying transcriptional up-regulation of drug transporter genes remains elusive. Employing Saccharomyces cerevisiae as a model, we analyzed here transcriptional regulation of the drug transporter gene PDR5 in a drug-resistant pdr1-3 strain. This mutant bears a gain-of-function mutation in PDR1, which encodes a transcriptional activator for PDR5. Similar to the well studied model gene GAL1, we provide evidence showing that PDR5 belongs to a group of genes whose transcription requires the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex. We also show that the drugindependent PDR5 transcription is associated with enhanced promoter occupancy of coactivator complexes, including SAGA, Mediator, chromatin remodeling SWI/ SNF complex, and TATA-binding protein. Analyzed by chromatin immunoprecipitations, loss of contacts between histones and DNA occurs at both promoter and coding sequences of PDR5. Consistently, micrococcal nuclease susceptibility analysis revealed altered chromatin structure at the promoter and coding sequences of PDR5. Our data provide molecular description of the changes associated with constitutive PDR5 transcription, and reveal the molecular mechanism underlying drug-independent transcriptional up-regulation of PDR5.Transcriptional regulation of the ATP binding cassette (ABC) transporter genes plays a pivotal role in the development of a drug resistance phenotype in mammalian (1, 2) and yeast cells (3-5). Constitutive transcriptional up-regulation of drug transporter genes occurs in certain mutations involving various transcriptional activators. However, the molecular mechanism underlying this enhanced transcription is not fully understood.In Saccharomyces cerevisiae, the multiple/pleiotropic drug resistance (MDR/PDR) phenotype is primarily regulated via two transcriptional activators encoded by homologous PDR1 and PDR3 genes. These factors are responsible for activating the majority of drug transporter genes, including PDR5 (5-7). Both activators belong to the Gal4 superfamily with the Zn2Cys6 DNA binding domain (8). The amino-terminal of their DNA binding domains recognize promoters with the Pdr1/Pdr3 response element (PDRE), 1 5Ј-TCCGCGGA-3Ј (9), such as that with PDR5.The Pdr5 transporter belongs to the ABC transporter superfamily. In the drug-resistant pdr1-3 and pdr3-7 strains, PDR5 transcription is the highest among target genes activated by Pdr1 and Pdr3 (10). The pdr1-3 and pdr3-7 strains are analogous to other mutants bearing gain-of-function mutations in PDR1 (11) and PDR3 (12) that up-regulate PDR5 transcription. The pdr1-3 allele bears a F815S mutation located near the transcription activation domain at the COOH terminus of Pdr1, suggesting that the mutation may alter the function of the activation domain.Activation of transcription in eukaryotes is mainly controlled by activator-mediated recruitments of transcription fact...

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Transcriptional regulators of the human multidrug resistance 1 gene: recent views

Cited by 158 publications

References 54 publications

Depletion of mitochondrial DNA up-regulates the expression of MDR1 gene via an increase in mRNA stability

Depletion of mitochondrial DNA up-regulates the expression of MDR1 gene via an increase in mRNA stability

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

On the Mechanism of Constitutive Pdr1 Activator-mediated PDR5 Transcription in Saccharomyces cerevisiae

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