Redundancy of biological regulation as the basis of emergence of multidrug resistance Journal Article


Authors: Shtil, A. A.; Azare, J.
Article Title: Redundancy of biological regulation as the basis of emergence of multidrug resistance
Abstract: Active efflux of xenobiotics is a major mechanism of cell adaptation to environmental stress. The ATP-dependent transmembrane transporter P-glycoprotein (Pgp) confers long-term cell survival in the presence of different toxins, including anticancer drugs (this concept is referred to as multidrug resistance, or MDR). The vital importance of this mechanism for cell survival dictates the reliability and promptness of its acquisition. To fulfill this requirement, the MDR1 gene that encodes Pgp in humans must be readily upregulated in cells that express low to null levels of MDR1 mRNA prior to stress. The MDR1 gene and a stable MDR phenotype can be induced after short-term exposure of cells to a variety of cues. This effect is implemented by activation of MDR1 transcription and mRNA stabilization. The MDR1 message abundance is regulated by mechanisms generally involved in stress response, namely activation of phospholipase C, protein kinase C and mitogen-activated protein kinase cascades, mobilization of intracellular Ca2+, and nuclear factor kappa B activation. Furthermore, the proximal MDR1 promoter sites critical for induction are not unique for the MDR1 gene; they are common regulatory elements in eukaryotic promoters. Moreover, MDR1 induction can result from activation of (an) intermediate gene(s) whose product(s), in turn, directly activate(s) the MDR1 promoter and/or cause(s) mRNA stabilization. Redundancy of signal transduction and transcriptional mechanisms is the basis for the virtually ubiquitous inducibility of the MDR1 gene. Thus, the complex network of MDR1 regulation ensures rapid emergence of pleiotropic resistance in cells. © 2005 Elsevier Inc.
Keywords: signal transduction; mitogen activated protein kinase; protein expression; promoter region; genetics; histone deacetylase inhibitor; review; nonhuman; antineoplastic agents; antineoplastic agent; phenotype; metabolism; gene; cell survival; cell function; gene overexpression; gene expression; transcription factor; calcium; vincristine; immunoglobulin enhancer binding protein; enzyme activation; physiology; transcription factors; gene expression regulation; antiinfective agent; regulatory mechanism; messenger rna; rna, messenger; eukaryota; chromatin; nf-kappa b; dactinomycin; mitogen activated protein kinase 1; mitogen activated protein kinase 3; gene control; 5 aza 2' deoxycytidine; protein kinase c; i kappa b kinase gamma; mitogen-activated protein kinases; lipid metabolism; calcium cell level; multidrug resistance; pleiotropy; p-glycoprotein; leukemia cell line; phorbol ester; trichostatin a; null allele; drug resistance, multiple; protein kinase c inhibitor; glycoprotein p; multidrug resistance protein 1; i kappa b; calcium ion; dna methyltransferase inhibitor; pyrrolidine dithiocarbamate; xenobiotic agent; promoter regions (genetics); i kappa b kinase inhibitor; phospholipase c; anticancer drugs; adenosine triphosphate dependent proteinase; salicylic acid derivative; tosylphenylalanyl chloromethyl ketone; genes, mdr
Journal Title: International Review of Cytology
Volume: 246
ISSN: 0074-7696
Publisher: Elsevier Inc.  
Date Published: 2005-01-01
Start Page: 1
End Page: 29
Language: English
DOI: 10.1016/s0074-7696(05)46001-5
PUBMED: 16164965
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 20" - "Export Date: 24 October 2012" - "CODEN: IRCYA" - "Source: Scopus"
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  1. Janeen R Azare
    7 Azare