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RSK-Mediated Phosphorylation in the C/EBP beta Leucine Zipper Regulates DNA Binding, Dimerization, and Growth Arrest Activity

  1. Author:
    Lee, S.
    Shuman, J. D.
    Guszczynski, T.
    Sakchaisri, K.
    Sebastian, T.
    Copeland, T. D.
    Miller, M.
    Cohen, M. S.
    Taunton, J.
    Smart, R. C.
    Xiao, Z.
    Yu, L. R.
    Veenstra, T. D.
    Johnson, P. F.

  2. Author Address

    [Lee, Sook; Shuman, Jon D.; Sakchaisri, Krisada; Sebastian, Thomas; Johnson, Peter F.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. [Guszczynski, Tad; Copeland, Terry D.] NCI, Lab Cell & Dev Signaling, Ctr Canc Res, Frederick, MD 21702 USA. [Miller, Maria] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Cohen, Michael S.; Taunton, Jack] Univ Calif San Francisco, Program Chem & Chem Biol, San Francisco, CA 94143 USA. [Cohen, Michael S.; Taunton, Jack] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Smart, Robert C.] N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. [Xiao, Zhen; Yu, Li-Rong; Veenstra, Timothy D.] SAIC Frederick Inc, Adv Technol Program, Lab Prote & Analyt Technol, Frederick, MD 21702 USA.;Johnson, PF, NCI, Lab Canc Prevent, Ctr Canc Res, Bldg 539,Room 122, Frederick, MD 21702 USA.;johnsope@mail.nih.gov
    1. Year: 2010
    2. Date: Jun
  2. Journal: Molecular and Cellular Biology
    1. 30
    2. 11
    3. Pages: 2621-2635
  4. Type of Article: Article
  5. ISSN: 0270-7306
  1. Abstract:

    The bZIP transcription factor C/EBP beta is a target of Ras signaling that has been implicated in Ras-induced transformation and oncogene-induced senescence (OIS). To gain insights into Ras-C/EBP beta signaling, we investigated C/EBP beta activation by oncogenic Ras. We show that C/EBP beta DNA binding is autorepressed and becomes activated by the Ras-Raf-MEK-ERK-p90(RSK) cascade. Inducible phosphorylation by RSK on Ser273 in the leucine zipper was required for DNA binding. In addition, three other modifications (phosphorylation on Tyr109 [p-Tyr109], p-Ser111, and monomethylation of Arg114 [me-Arg114]) within an N-terminal autoinhibitory domain were important for Ras-induced C/EBP beta activation and cytostatic activity. Apart from its role in DNA binding, Ser273 phosphorylation also creates an interhelical g <-> e ' salt bridge with Lys268 that increases attractive electrostatic interactions between paired leucine zippers and promotes homodimerization. Mutating Ser273 to Ala or Lys268 to Glu decreased C/EBP beta homodimer formation, whereas heterodimerization with C/EBP gamma was relatively unaffected. The S273A substitution also reduced the antiproliferative activity of C/EBP beta in Ras(V12)-expressing fibroblasts and decreased binding to target cell cycle genes, while a phosphomimetic substitution (S273D) maintained growth arrest function. Our findings identify four novel C/EBP beta-activating modifications, including RSK-mediated phosphorylation of a bifunctional residue in the leucine zipper that regulates DNA binding and homodimerization and thereby promotes cell cycle arrest.

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External Sources

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  2. DOI: 10.1128/mcb.00782-09
  3. View record in Web of Science®
  4. WOS: 000277558300005

Library Notes

  1. Fiscal Year: FY2009-2010
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