Regulation of arsenic trioxide-induced cellular responses by Mnk1 and Mnk2

被引:32
作者
Dolniak, Blazej [1 ,2 ,3 ]
Katsoulidis, Efstratios [1 ,2 ,3 ]
Carayol, Nathalie [1 ,2 ,3 ]
Altman, Jessica K. [1 ,2 ,3 ]
Redig, Amanda J. [1 ,2 ,3 ]
Tallman, Martin S. [1 ,2 ,3 ]
Ueda, Takeshi [4 ]
Watanabe-Fukunaga, Rie [4 ]
Fukunaga, Rikiro [4 ]
Platanias, Leonidas C. [1 ,2 ,3 ]
机构
[1] Northwestern Univ, Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA
[2] Northwestern Univ, Sch Med, Div Hematol Oncol, Dept Med, Chicago, IL 60611 USA
[3] Jesse Brown Vet Affairs Med Ctr, Chicago, IL 60611 USA
[4] Osaka Univ, Genet Lab, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan
关键词
D O I
10.1074/jbc.M708816200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Arsenic trioxide (As2O3) 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 As2O3 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 p38 alpha 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.
引用
收藏
页码:12034 / 12042
页数:9
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