P-glycoprotein (MDR1) expression in leukemic cells is regulated at two distinct steps, mRNA stabilization and translational initiation.

2.50
Hdl Handle:
http://hdl.handle.net/10541/82257
Title:
P-glycoprotein (MDR1) expression in leukemic cells is regulated at two distinct steps, mRNA stabilization and translational initiation.
Authors:
Yague, Ernesto; Armesilla, Angel L; Harrison, Georgina; Elliott, James; Sardini, Alessandro; Higgins, Christopher F; Raguz, Selina
Abstract:
Multidrug 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.
Affiliation:
Medical Research Council Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom.
Citation:
P-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.
Journal:
The Journal of Biological Chemistry
Issue Date:
21-Mar-2003
URI:
http://hdl.handle.net/10541/82257
DOI:
10.1074/jbc.M211093200
PubMed ID:
12525496
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
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.en
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

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