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c‐Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin‐based therapy
Author(s) -
GalanMoya Eva M.,
HernandezLosa Javier,
Aceves Luquero Clara I.,
de la CruzMorcillo Miguel A.,
RamírezCastillejo Carmen,
CallejasValera Juan L.,
Arriaga Angel,
Aranburo Antonio Fernandez,
Cajal Santiago Ramón y,
Silvio Gutkind J.,
SánchezPrieto Ricardo
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23063
Subject(s) - tyrosine kinase , mapk/erk pathway , cancer research , cisplatin , abl , p38 mitogen activated protein kinases , tyrosine kinase inhibitor , imatinib mesylate , chemistry , kinase , myeloid leukemia , signal transduction , imatinib , microbiology and biotechnology , medicine , biology , chemotherapy , cancer
Abstract Activation of p38 MAPK is a critical requisite for the therapeutics activity of the antitumor agent cisplatin. In this sense, a growing body of evidences supports the role of c‐Abl as a major determinant of p38 MAPK activation, especially in response to genotoxic stress when triggered by cisplatin. Here, we demonstrate that p38 MAPK activation in response to cisplatin does not require the tyrosine kinase activity of c‐Abl. Indeed, c‐Abl can activate the p38 MAPK signaling pathway by a mechanism that is independent of its tyrosine kinase activity, but that instead involves the ability of c‐Abl to increase the stability of MKK6. Similar results were obtained in chronic myeloid leukemia‐derived cell lines, in which a chimeric Bcr/Abl protein mimics the effects of c‐Abl overexpression on p38 MAPK activation. These findings may explain why a clinically used c‐Abl inhibitor, imatinib mesylate, fails to inhibit the p38 MAPK pathway alone or in combination with cisplatin, and provide evidence of a novel signaling mechanism in which these antitumor agents act. © 2007 Wiley‐Liss, Inc.