Regulation of arsenic trioxide-induced cellular responses by Mnk1 and Mnk2.
Arsenic trioxide (As(2)O(3)) is a potent inducer of apoptosis of malignant cells in vitro and in vivo, but the precise mechanisms by which it mediates such effects are not well defined. We provide evidence that As(2)O(3) induces phosphorylation/activation of the MAPK signal-integrating kinases (Mnks) 1 and 2 in leukemia cell lines. Such activation is defective in cells with targeted disruption of the p38alpha MAPK gene, indicating that it requires upstream engagement of the p38 MAPK pathway. Studies using Mnk1(-/-) or Mnk2(-/-), or double Mnk1(-/-)Mnk2(-/-) knock-out cells, establish that activation of Mnk1 and Mnk2 by arsenic trioxide regulates downstream phosphorylation of the eukaryotic initiation factor 4E at Ser-209. Importantly, arsenic-induced apoptosis is enhanced in cells with targeted disruption of the Mnk1 and/or Mnk2 genes, suggesting that these kinases are activated in a negative-feedback regulatory manner, to control generation of arsenic trioxide responses. Consistent with this, pharmacological inhibition of Mnk activity enhances the suppressive effects of arsenic trioxide on primary leukemic progenitors from patients with acute leukemias. Taken together, these findings indicate an important role for Mnk kinases, acting as negative regulators for signals that control generation of arsenic trioxide-dependent apoptosis and antileukemic responses.
Dolniak
Blazej
B
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Department of Medicine, Northwestern University Medical School, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60611, USA.
Katsoulidis
Efstratios
E
Carayol
Nathalie
N
Altman
Jessica K
JK
Redig
Amanda J
AJ
Tallman
Martin S
MS
Ueda
Takeshi
T
Watanabe-Fukunaga
Rie
R
Fukunaga
Rikiro
R
Platanias
Leonidas C
LC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001752:Blast Crisis / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D018390:Gene Targeting; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000473:pathology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014410:Tumor Stem Cell Assay
D001152:Arsenicals; D004791:Enzyme Inhibitors; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D010087:Oxides; C491395:MKNK1 protein, human; C106281:Mknk1 protein, mouse; C106282:Mknk2 protein, mouse; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D000077237:Arsenic Trioxide