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Wolverhampton Intellectual Repository and E-Theses > Research Institutes > Research Institute in Healthcare Science > Molecular Pharmacology Research Group > P-glycoprotein (MDR1) expression in leukemic cells is regulated at two distinct steps, mRNA stabilization and translational initiation.

Please use this identifier to cite or link to this item: http://hdl.handle.net/2436/7693
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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
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
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.
Type: Article
Language: en
Keywords: P-glycoprotein (MDR1)
Leukemic cells
Myeloid leukemia
Multidrug resistance
ISSN: 0021-9258
Appears in Collections: Molecular Pharmacology Research Group

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