Activation of the mitogen- and stress-activated kinase 1 by arsenic trioxide.
Arsenic trioxide (As2O3) is a potent inducer of apoptosis of leukemic cells in vitro and in vivo, but the precise mechanisms by which it mediates such effects are not well defined. We provide evidence that As2O3 induces activation of the mitogen- and stress-activated kinase 1 (MSK1) and downstream phosphorylation of its substrate, histone H3, in leukemia cell lines. Such activation requires upstream engagement of p38 MAPK, as demonstrated by experiments using pharmacological inhibitors of p38 or p38alpha knock-out cells. Arsenic-induced apoptosis was enhanced in cells in which MSK1 expression was decreased using small interfering RNA and in Msk1 knock-out mouse embryonic fibroblasts, suggesting that this kinase is activated in a negative feedback regulatory manner to regulate As2O3 responses. Consistent with this, pharmacological inhibition of MSK1 enhanced the suppressive effects of As2O3 on the growth of primary leukemic progenitors from chronic myelogenous leukemia patients. Altogether, these findings indicate an important role for MSK1 downstream of p38 in the regulation of As2O3 responses.
Kannan-Thulasiraman
Padma
P
Robert H. Lurie Comprehensive Cancer Center and the Division of Hematology/Oncology, Department of Medicine, Northwestern University Medical School, and Lakeside VA Hospital Chicago, Illinois 60611, USA.
Katsoulidis
Efstratios
E
Tallman
Martin S
MS
Arthur
J Simon C
JS
Platanias
Leonidas C
LC
D000818:Animals; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D006657:Histones / Q000737:chemistry; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010087:Oxides / Q000494:pharmacology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D001152:Arsenicals; D006657:Histones; D010087:Oxides; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; D000077237:Arsenic Trioxide