title: Modulation of the p38 MAPK (mitogen-activated protein kinase) pathway through Bcr/Abl: implications in the cellular response to Ara-C.
abstract: The chimaeric protein Bcr/Abl, the hallmark of chronic myeloid leukaemia, has been connected with several signalling pathways, such as those involving protein kinase B/Akt, JNK (c-Jun N-terminal kinase) or ERKs (extracellular-signal-regulated kinases) 1 and 2. However, no data about the p38 MAPK (mitogen-activated protein kinase) have been reported. Here, we present evidence showing that Bcr/Abl is able to modulate this signalling pathway. Transient transfection experiments indicated that overexpression of Bcr/Abl in 293T cells is able to activate p38 MAPK or induce p73 stabilization, suggesting that c-Abl and Bcr/Abl share some biological substrates. Interestingly, the control exerted by Bcr/Abl on the p38 MAPK pathway was not only mediated by the tyrosine kinase activity of Bcr/Abl, as the use of STI571 demonstrated. In fact, Bcr alone was able to induce p38 MAPK activation specifically through MKK3 (MAP kinase kinase 3). Supporting these observations, chronic myeloid leukaemia-derived K562 cells or BaF 3 cells stably transfected with Bcr/Abl showed higher levels of phosphorylated p38 MAPK compared with Bcr/Abl-negative cells. While Bcr/Abl-negative cells activated p38 MAPK in response to Ara-C (1-beta-D-arabinofuranosylcytosine), Bcr/Abl-positive cells were unable to activate p38 MAPK, suggesting that the p38 MAPK pathway is not sensitive to Abl-dependent stimuli in Bcr/Abl-positive cells. Our results demonstrate that the involvement of Bcr/Abl in the p38 MAPK pathway is a key mechanism for explaining resistance to Ara-C, and could provide a clue for new therapeutic approaches based on the use of specific Abl inhibitors.
authors.affiliation: Immunology Department, Hospital Universitario Puerta de Hierro, 28035 Madrid, Spain.
authors.forename: Víctor Javier
authors.initials: VJ
authors.lastname: Sánchez-Arévalo Lobo
authors.forename: Clara Isabel
authors.initials: CI
authors.lastname: Aceves Luquero
authors.forename: Luis
authors.initials: L
authors.lastname: Alvarez-Vallina
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Tipping
authors.forename: Juan Guinea
authors.initials: JG
authors.lastname: Viniegra
authors.forename: Javier
authors.initials: J
authors.lastname: Hernández Losa
authors.forename: Carlos
authors.initials: C
authors.lastname: Parada Cobo
authors.forename: Eva María
authors.initials: EM
authors.lastname: Galán Moya
authors.forename: Jorge
authors.initials: J
authors.lastname: Gayoso Cruz
authors.forename: Junia V
authors.initials: JV
authors.lastname: Melo
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramón y Cajal
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sánchez-Prieto
mesh_terms: D001549:Benzamides; D002460:Cell Line; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism* / Q000502:physiology; D016147:Genes, Tumor Suppressor; D006801:Humans; D000068877:Imatinib Mesylate; D007668:Kidney / Q000737:chemistry / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D020298:U937 Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D001549:Benzamides; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010879:Piperazines; D011743:Pyrimidines; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D003561:Cytarabine; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; D048051:p38 Mitogen-Activated Protein Kinases