IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
MRP4 regulates cAMP levels and controls leukemia cell proliferation and differentiation
Autor/es:
COPSEL S; GARCIA C; DIEZ F; VERMEULEN M; RUSSEL FGM; SHAYO C; DAVIO C
Lugar:
Los Cocos-Cordoba
Reunión:
Simposio; The First South American spring Symposium in Signal Trasducction and Molecular Medicine. (SISTAM 2010).; 2010
Resumen:
Increased intracellular cAMP concentration
play a well established role in leukemic cell
maturation. We previously reported that U937
cells stimulated by histamine H2 receptor
agonists, despite a robust increase in cAMP,
fail to mature because of rapid H2 receptor
desensitization and phosphodiesterase (PDE)
activation. Here we show that intracellular
cAMP levels in different human AML cell
lines are also regulated by multidrug resistanceassociated proteins (MRPs),
particularly MRP4. U937, HL-60 and KG-1a cells, exposed to amthamine (H2
receptor agonist), augmented intracellular cAMP concentration with a concomitant
increase in the efflux. Extrusion of cAMP was ATP-dependent and
probenecid-sensitive, supporting that the
transport was MRP mediated. Amthamine
stimulation, combined with PDE4 and MRP
inhibition, induced maximal cell arrest
proliferation. Knock-down strategy by shRNA
revealed that this process was mediated by
MRP4. Furthermore blockade by probenecid or
MRP4 knock-down showed that increased
intracellular cAMP levels induce maturation
in U937 cells. These findings confirm the key
role of intracellular cAMP levels in
leukemic cell maturation and provide the first evidence
that MRP4 may represent
a new potential target for leukemia differentiation therapy.