TY - JOUR
T1 - A Conserved MST-FOXO Signaling Pathway Mediates Oxidative-Stress Responses and Extends Life Span
AU - Lehtinen, Maria K.
AU - Yuan, Zengqiang
AU - Boag, Peter R.
AU - Yang, Yue
AU - Villén, Judit
AU - Becker, Esther B.E.
AU - DiBacco, Sara
AU - de la Iglesia, Núria
AU - Gygi, Steven
AU - Blackwell, T. Keith
AU - Bonni, Azad
N1 - Funding Information:
We thank J. Blenis, G. Corfas, A. Hart, and L.-H. Tsai for helpful discussions; members of the Bonni laboratory for critical reading of the manuscript and helpful discussions; Z. Zheng for statistical advice; M. Smidt for providing GFP-FOXO3; J. Avruch for MST plasmids; J. Chernoff for MST1 antibodies; J. Ham for pGL3-BIM; Y. Shi for His-DAF-16; A. Fire for pPD95.75; G. Ruvkun for the daf-2 and daf-16 RNAi constructs; and W. Mohler for Pmyo-3::myo-3::gfp nematodes. This work was supported by NIH grants NS41021 (A.B.) and GM62891 (T.K.B.) and fellowships from the NSF (M.K.L. and Y.Y.), Glenn/AFAR (M.K.L.), the Albert J. Ryan Foundation (M.K.L. and E.B.E.B.), the Lefler Foundation (Z.Y.), and the Myra Reinhard Family Foundation (P.R.B.). A.B. is the recipient of a fellowship from the Alfred P. Sloan Foundation, a Robert H. Ebert Clinical Scholar Award from the Esther A. and Joseph Klingenstein Fund, an EJLB Foundation award, and a Sidney Kimmel Foundation Award. We apologize to authors whose work was not cited owing to space limitations.
PY - 2006/6/2
Y1 - 2006/6/2
N2 - Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. Here, we demonstrate that the protein kinase MST1 mediates oxidative-stress-induced cell death in primary mammalian neurons by directly activating the FOXO transcription factors. MST1 phosphorylates FOXO proteins at a conserved site within the forkhead domain that disrupts their interaction with 14-3-3 proteins, promotes FOXO nuclear translocation, and thereby induces cell death in neurons. We also extend the MST-FOXO signaling link to nematodes. Knockdown of the C. elegans MST1 ortholog CST-1 shortens life span and accelerates tissue aging, while overexpression of cst-1 promotes life span and delays aging. The cst-1-induced life-span extension occurs in a daf-16-dependent manner. The identification of the FOXO transcription factors as major and evolutionarily conserved targets of MST1 suggests that MST kinases play important roles in diverse biological processes including cellular responses to oxidative stress and longevity.
AB - Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. Here, we demonstrate that the protein kinase MST1 mediates oxidative-stress-induced cell death in primary mammalian neurons by directly activating the FOXO transcription factors. MST1 phosphorylates FOXO proteins at a conserved site within the forkhead domain that disrupts their interaction with 14-3-3 proteins, promotes FOXO nuclear translocation, and thereby induces cell death in neurons. We also extend the MST-FOXO signaling link to nematodes. Knockdown of the C. elegans MST1 ortholog CST-1 shortens life span and accelerates tissue aging, while overexpression of cst-1 promotes life span and delays aging. The cst-1-induced life-span extension occurs in a daf-16-dependent manner. The identification of the FOXO transcription factors as major and evolutionarily conserved targets of MST1 suggests that MST kinases play important roles in diverse biological processes including cellular responses to oxidative stress and longevity.
UR - http://www.scopus.com/inward/record.url?scp=33646934067&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2006.03.046
DO - 10.1016/j.cell.2006.03.046
M3 - Article
C2 - 16751106
AN - SCOPUS:33646934067
SN - 0092-8674
VL - 125
SP - 987
EP - 1001
JO - Cell
JF - Cell
IS - 5
ER -