Loading...
P-glycoprotein (MDR1) expression in leukemic cells is regulated at two distinct steps, mRNA stabilization and translational initiation
Yague, Ernesto Harrison, Georgina Elliott, James Sardini, Alessandro Higgins, Christopher F. Raguz, Selina
Yague, Ernesto
Harrison, Georgina
Elliott, James
Sardini, Alessandro
Higgins, Christopher F.
Raguz, Selina
Editors
Other contributors
Affiliation
Epub Date
Issue Date
2003-03-31
Submitted date
Alternative
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
Yagüe, E., Armesilla, A.L., Harrison, G. et al. (2003) P-glycoprotein (MDR1) expression in leukemic cells is regulated at two distinct steps, mRNA stabilization and translational initiation. Journal of Biological Chemistry, 278(12), pp. 10344-10352.
Journal
Research Unit
PubMed ID
12525496
PubMed Central ID
Embedded videos
Additional Links
Type
Journal article
Language
en
Description
Series/Report no.
ISSN
0021-9258