Chemical Genetics Identify eIF2α Kinase Heme Regulated Inhibitor as Anti-Cancer Target

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Chemical Genetics Identify eIF2α Kinase Heme Regulated Inhibitor as Anti-Cancer Target

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Title: Chemical Genetics Identify eIF2α Kinase Heme Regulated Inhibitor as Anti-Cancer Target
Author: Chen, Ting; Ozel, Duygu; Qiao, Yuan; Harbinski, Fred; Chen, Limo; Denoyelle, Séverine; He, Xiaoying; Zvereva, Nela; Supko, Jeffrey G.; Chorev, Michael; Halperin, Jose A.; Aktas, Bertal H.

Note: Order does not necessarily reflect citation order of authors.

Citation: Chen, T., D. Ozel, Y. Qiao, F. Harbinski, L. Chen, S. Denoyelle, X. He, et al. 2013. “Chemical Genetics Identify eIF2α Kinase Heme Regulated Inhibitor as Anti-Cancer Target.” Nature chemical biology 7 (9): 610-616. doi:10.1038/nchembio.613. http://dx.doi.org/10.1038/nchembio.613.
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Abstract: Translation initiation plays a critical role in cellular homeostasis, proliferation, differentiation and malignant transformation. Consistently, increasing the abundance of the eIF2·GTP·Met-tRNAi translation initiation complex transforms normal cells and contributes to cancer initiation and the severity of some anemia. The chemical modifiers of the eIF2·GTP·Met-tRNAi ternary complex are therefore invaluable tools for studying its role in the pathobiology of human disorders and for determining if this complex can be pharmacologically targeted for therapeutic purposes. Using a cell based assay, we identified N,N’-diarylureas as novel inhibitors of the ternary complex abundance. Direct functional-genetics and biochemical evidence demonstrated that the N,N’-diarylureas activate heme regulated inhibitor kinase, thereby phosphorylate eIF2α and reduce abundance of the ternary complex. Using tumor cell proliferation in vitro and tumor growth in vivo as paradigms, we demonstrate that N,N’-diarylureas are potent and specific tools for studying the role eIF2·GTP·Met-tRNAi ternary complex in the pathobiology of human disorders.
Published Version: doi:10.1038/nchembio.613
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684262/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:11708541
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