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/2436/7693
Title:
P-glycoprotein (MDR1) expression in leukemic cells is regulated at two distinct steps, mRNA stabilization and translational initiation.
Authors:
Yague, Ernesto; Armesilla, Angel Luis; 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.
Citation:
The Journal of Biological Chemistry, 278(12): 10344-10352
Publisher:
American Society for Biochemistry and Molecular Biology
Issue Date:
2003
URI:
http://hdl.handle.net/2436/7693
DOI:
10.1074/jbc.M211093200
PubMed ID:
12525496
Additional Links:
http://www.jbc.org/cgi/reprint/278/12/10344
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
Molecular Pharmacology Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorYague, Ernesto-
dc.contributor.authorArmesilla, Angel Luis-
dc.contributor.authorHarrison, Georgina-
dc.contributor.authorElliott, James-
dc.contributor.authorSardini, Alessandro-
dc.contributor.authorHiggins, Christopher F.-
dc.contributor.authorRaguz, Selina-
dc.date.accessioned2007-01-23T15:20:47Z-
dc.date.available2007-01-23T15:20:47Z-
dc.date.issued2003-
dc.identifier.citationThe Journal of Biological Chemistry, 278(12): 10344-10352en
dc.identifier.issn0021-9258-
dc.identifier.pmid12525496-
dc.identifier.doi10.1074/jbc.M211093200-
dc.identifier.urihttp://hdl.handle.net/2436/7693-
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.format.extent378854 bytes-
dc.format.mimetypeapplication/pdf-
dc.language.isoenen
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen
dc.relation.urlhttp://www.jbc.org/cgi/reprint/278/12/10344en
dc.subjectP-glycoprotein (MDR1)en
dc.subjectLeukemic cellsen
dc.subjectMyeloid leukemiaen
dc.subjectMultidrug resistanceen
dc.titleP-glycoprotein (MDR1) expression in leukemic cells is regulated at two distinct steps, mRNA stabilization and translational initiation.en
dc.typeArticleen
dc.format.digYES-

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