title: Regulation of the mitogen-activated protein kinase kinase (MEK)-1 by NAD(+)-dependent deacetylases.
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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Yeung
authors.affiliation: Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Ramsey
authors.affiliation: Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Popko-Scibor
authors.affiliation: Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Allison
authors.affiliation: Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA, USA.
authors.forename: L G
authors.initials: LG
authors.lastname: Gray
authors.affiliation: Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Shin
authors.affiliation: Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, East Carolina University, Greenville, NC, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Department of Biochemistry and Molecular Genetics, The University of Virginia, Charlottesville, VA, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Mayo
mesh_terms: D000107:Acetylation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D056564:Sirtuin 1 / Q000096:biosynthesis* / Q000235:genetics; D056565:Sirtuin 2 / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D009243:NAD; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2