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Regulation of the mitogen-activated protein kinase kinase (MEK)-1 by NAD+-dependent deacetylases

Oncogene volume 34, pages 798–804 (2015)Cite this article

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Abstract

Sirtuins are class III deacetylases that regulate many essential processes, including cellular stress, genome stability and metabolism. Although these NAD+-dependent deacetylases control adaptive cellular responses, identification of sirtuin-regulated signaling targets remain under-studied. Here, we demonstrate that acetylation of the mitogen-activated protein kinase kinase-1 (MEK1) stimulates its kinase activity, and that acetylated MEK1 is under the regulatory control of the sirtuin family members SIRT1 and SIRT2. Treatment of cells with sirtuin inhibitors, or siRNA knockdown of SIRT1 or SIRT2 proteins, increases MEK1 acetylation and subsequent phosphorylation of the extracellular signal-regulated kinase. Generation of an acetyl-specific MEK1 antibody demonstrates that endogenous acetylated MEK1 is extensively enriched in the nucleus following epidermal growth factor stimulation. An acetyl-mimic of MEK1 increases inappropriate growth properties, suggesting that acetylation of MEK1 has oncogenic potential.

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Acknowledgements

 We thank Drs JS Smith, PT Stukenberg, JJ Wamsley and Ms A Sherman for scientific and editorial review. HA-MEK1, HA-MEK1(S218/222D) and Flag-ERK1 were gifts from Dr M Weber, University of Virginia. p300 was provided by Dr D Livingston, Dana-Farber Cancer Institute. Gal4-ELK1 was a gift from Dr C Der, University of North Carolina. V5-SIRT1 and Flag-SIRT2 were gifts from E Verdin, Gladstone Institute. The pBabe-puro vector was provided by Dr Robert Weinberg, Whitehead Institute, MIT. Work was supported by the National Cancer Institute (CA132580 and CA104397) to MWM, and CA110552 awarded to FY.

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  1. F Yeung and C S Ramsey: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA, USA

    F Yeung, C S Ramsey, A E Popko-Scibor, D F Allison, L G Gray, M Shin, M Kumar, D Li & M W Mayo

  2. Department of Microbiology and Immunology, East Carolina University, Greenville, NC, USA

    J A McCubrey

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  1. F Yeung
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Correspondence to M W Mayo.

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Yeung, F., Ramsey, C., Popko-Scibor, A. et al. Regulation of the mitogen-activated protein kinase kinase (MEK)-1 by NAD+-dependent deacetylases. Oncogene 34, 798–804 (2015). https://doi.org/10.1038/onc.2014.39

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