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J. Biol. Chem., Vol. 278, Issue 12, 10344-10352, March 21, 2003
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From the 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 naïve 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.
P-glycoprotein (MDR1) Expression in Leukemic Cells
Is Regulated at Two Distinct Steps, mRNA Stabilization and
Translational Initiation*
,,,,, and
Medical Research Council Clinical
Sciences Centre, Imperial College Faculty of Medicine, Hammersmith
Hospital Campus, Du Cane Road, London W12 0NN and § Cancer
Research UK, Paterson Institute for Cancer Research Cell Regulation
Laboratory, Manchester M20 4BX, United Kingdom
*
This work was supported by the Medical Research Council UK
and Cancer Research UK.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
44-20-8383-8269; Fax: 44-20-8383-8337; E-mail:
s.raguz@csc.mrc.ac.uk.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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