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Copsel, S.; Garcia, C.; Diez, F.; Vermeulem, M.; Baldi, A.; Bianciotti, L.G.; Russel, F.G.M.; Shayo, C.; Davio, C. "Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation" (2011) Journal of Biological Chemistry. 286(9):6979-6988
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Abstract:

Increased intracellular cAMP concentration plays a well established role in leukemic cell maturation. We previously reported that U937 cells stimulated by 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 intracellularcAMPlevels not only in U937 cells but also in other acute myeloid leukemia cell lines are also regulated by multidrug resistance-associated proteins (MRPs), particularly MRP4. U937, HL-60, and KG-1a cells, exposed to amthamine (H2-receptor agonist), augmented intra-cellular 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. Cells exposed to amthamine and the PDE4 inhibitor showed enhanced cAMP extrusion, but this response was inhibited by MRP blockade. Amthamine stimulation, combined with PDE4 and MRP inhibition, induced maximal cell arrest proliferation. Knockdown strategy by shRNA revealed that this process was mediated by MRP4. Furthermore, blockade by probenecid or MRP4 knockdown 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. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Registro:

Documento: Artículo
Título:Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation
Autor:Copsel, S.; Garcia, C.; Diez, F.; Vermeulem, M.; Baldi, A.; Bianciotti, L.G.; Russel, F.G.M.; Shayo, C.; Davio, C.
Filiación:Departamento de Farmacología, Facultad de Farmacia Y Bioquímica, Universidad de Buenos Aires, 1113 Buenos Aires, Argentina
Laboratorio de Patología y Farmacología Molecular, Instituto de Biología Y Medicina Experimental, 1428 Buenos Aires, Argentina
Consejo Nacional de Investigaciones Científicas Y Técnicas, Argentina
Departamento de Inmunología, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, 1425 Buenos Aires, Argentina
Departamento de Ciencias Biológicas, Facultad de Farmacia Y Bioquímica, Universidad de Buenos Aires, 1113 Buenos Aires, Argentina
Department of Pharmacology and Toxicology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6525 HP Nijmegen, Netherlands
Palabras clave:Acute myeloid leukemia; Cellular levels; Human leukemia cells; Intracellular cAMP; Leukemic cells; Multidrug resistance; PDE4 inhibitor; Phosphodiesterases; Probenecid; U937 cell; Cell culture; Cell proliferation; Diseases; Extrusion; Fetal monitoring; adenosine triphosphate; amthamine; cyclic AMP; multidrug resistance protein; multidrug resistance protein 4; phosphodiesterase IV inhibitor; probenecid; short hairpin RNA; acute granulocytic leukemia; article; cell cycle arrest; cell differentiation; cell maturation; cell proliferation; cell strain HL 60; cell strain U937; controlled study; human; human cell; leukemia cell; leukemia cell line; priority journal; protein transport; Cell Differentiation; Cell Division; Cyclic AMP; Drug Design; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Multidrug Resistance-Associated Proteins; Phosphodiesterase 4 Inhibitors; Probenecid; RNA, Small Interfering; Rolipram; Signal Transduction; Thiazoles; U937 Cells
Año:2011
Volumen:286
Número:9
Página de inicio:6979
Página de fin:6988
DOI: http://dx.doi.org/10.1074/jbc.M110.166868
Título revista:Journal of Biological Chemistry
Título revista abreviado:J. Biol. Chem.
ISSN:00219258
CODEN:JBCHA
CAS:adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; amthamine, 142437-67-0; cyclic AMP, 60-92-4; multidrug resistance protein, 149200-37-3, 208997-77-7; multidrug resistance protein 4, 299244-49-8; probenecid, 57-66-9; ABCC4 protein, human; Cyclic AMP, 60-92-4; Multidrug Resistance-Associated Proteins; Phosphodiesterase 4 Inhibitors; Probenecid, 57-66-9; RNA, Small Interfering; Rolipram, 61413-54-5; Thiazoles; amthamine, 142437-67-0
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v286_n9_p6979_Copsel

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Citas:

---------- APA ----------
Copsel, S., Garcia, C., Diez, F., Vermeulem, M., Baldi, A., Bianciotti, L.G., Russel, F.G.M.,..., Davio, C. (2011) . Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation. Journal of Biological Chemistry, 286(9), 6979-6988.
http://dx.doi.org/10.1074/jbc.M110.166868
---------- CHICAGO ----------
Copsel, S., Garcia, C., Diez, F., Vermeulem, M., Baldi, A., Bianciotti, L.G., et al. "Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation" . Journal of Biological Chemistry 286, no. 9 (2011) : 6979-6988.
http://dx.doi.org/10.1074/jbc.M110.166868
---------- MLA ----------
Copsel, S., Garcia, C., Diez, F., Vermeulem, M., Baldi, A., Bianciotti, L.G., et al. "Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation" . Journal of Biological Chemistry, vol. 286, no. 9, 2011, pp. 6979-6988.
http://dx.doi.org/10.1074/jbc.M110.166868
---------- VANCOUVER ----------
Copsel, S., Garcia, C., Diez, F., Vermeulem, M., Baldi, A., Bianciotti, L.G., et al. Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation. J. Biol. Chem. 2011;286(9):6979-6988.
http://dx.doi.org/10.1074/jbc.M110.166868