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dc.contributor.authorYague, Ernesto
dc.contributor.authorArmesilla, Angel L
dc.contributor.authorHarrison, Georgina
dc.contributor.authorElliott, James
dc.contributor.authorSardini, Alessandro
dc.contributor.authorHiggins, Christopher F
dc.contributor.authorRaguz, Selina
dc.date.accessioned2009-09-23T10:27:46Z
dc.date.available2009-09-23T10:27:46Z
dc.date.issued2003-03-21
dc.identifier.citationP-glycoprotein (MDR1) expression in leukemic cells is regulated at two distinct steps, mRNA stabilization and translational initiation. 2003, 278 (12):10344-52 J. Biol. Chem.en
dc.identifier.issn0021-9258
dc.identifier.pmid12525496
dc.identifier.doi10.1074/jbc.M211093200
dc.identifier.urihttp://hdl.handle.net/10541/82257
dc.description.abstractMultidrug resistance in acute myeloid leukemia is often conferred by overexpression of P-glycoprotein, encoded by the MDR1 gene. We have characterized the key regulatory steps in the development of multidrug resistance in K562 myelogenous leukemic cells. Unexpectedly, up-regulation of MDR1 levels was not due to transcriptional activation but was achieved at two distinct post-transcriptional steps, mRNA turnover and translational regulation. The short-lived (half-life 1 h) MDR1 mRNA of naive cells (not exposed to drugs) was stabilized (half-life greater than 10 h) following short-term drug exposure. However, this stabilized mRNA was not associated with translating polyribosomes and did not direct P-glycoprotein synthesis. Selection for drug resistance, by long-term exposure to drug, led to resistant lines in which the translational block was overcome such that the stabilized mRNA was translated and P-glycoprotein expressed. The absence of a correlation between steady-state MDR1 mRNA and P-glycoprotein levels was not restricted to K562 cells but was found in other lymphoid cell lines. These findings have implications for the avoidance or reversal of multidrug resistance in the clinic.
dc.language.isoenen
dc.subjectLeukaemic Gene Expression Regulationen
dc.subject.meshGene Expression Regulation, Leukemic
dc.subject.meshGene Rearrangement
dc.subject.meshHumans
dc.subject.meshK562 Cells
dc.subject.meshP-Glycoprotein
dc.subject.meshProtein Biosynthesis
dc.subject.meshProtein Transport
dc.subject.meshRNA Processing, Post-Transcriptional
dc.subject.meshRNA, Messenger
dc.subject.meshTetradecanoylphorbol Acetate
dc.subject.meshTranscriptional Activation
dc.titleP-glycoprotein (MDR1) expression in leukemic cells is regulated at two distinct steps, mRNA stabilization and translational initiation.en
dc.typeArticleen
dc.contributor.departmentMedical Research Council Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom.en
dc.identifier.journalThe Journal of Biological Chemistryen
html.description.abstractMultidrug resistance in acute myeloid leukemia is often conferred by overexpression of P-glycoprotein, encoded by the MDR1 gene. We have characterized the key regulatory steps in the development of multidrug resistance in K562 myelogenous leukemic cells. Unexpectedly, up-regulation of MDR1 levels was not due to transcriptional activation but was achieved at two distinct post-transcriptional steps, mRNA turnover and translational regulation. The short-lived (half-life 1 h) MDR1 mRNA of naive cells (not exposed to drugs) was stabilized (half-life greater than 10 h) following short-term drug exposure. However, this stabilized mRNA was not associated with translating polyribosomes and did not direct P-glycoprotein synthesis. Selection for drug resistance, by long-term exposure to drug, led to resistant lines in which the translational block was overcome such that the stabilized mRNA was translated and P-glycoprotein expressed. The absence of a correlation between steady-state MDR1 mRNA and P-glycoprotein levels was not restricted to K562 cells but was found in other lymphoid cell lines. These findings have implications for the avoidance or reversal of multidrug resistance in the clinic.


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