Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation
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)...
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2011
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paper:paper_00219258_v286_n9_p6979_Copsel2023-06-08T14:43:33Z Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation 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 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. 2011 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v286_n9_p6979_Copsel http://hdl.handle.net/20.500.12110/paper_00219258_v286_n9_p6979_Copsel |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation |
| topic_facet |
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 |
| description |
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. |
| title |
Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation |
| title_short |
Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation |
| title_full |
Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation |
| title_fullStr |
Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation |
| title_full_unstemmed |
Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation |
| title_sort |
multidrug resistance protein 4 (mrp4/abcc4) regulates camp cellular levels and controls human leukemia cell proliferation and differentiation |
| publishDate |
2011 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v286_n9_p6979_Copsel http://hdl.handle.net/20.500.12110/paper_00219258_v286_n9_p6979_Copsel |
| _version_ |
1768544624155033600 |