Modulation of p53 C-terminal acetylation by mdm2, p14ARF, and cytoplasmic SirT2

Ingeborg M. M. van Leeuwen, Maureen Higgins, Johanna Campbell, Anna R. McCarthy, Marijke C. C. Sachweh, Ana Marin Navarro, Sonia Lain

    Research output: Contribution to journalArticlepeer-review

    29 Citations (Scopus)

    Abstract

    Acetylation of C-terminal lysine residues in the p53 tumor suppressor is associated with increased stability and transcription factor activity. The function, protein level, and acetylation of p53 are downregulated by mdm2, which in its turn is inhibited by the p14(ARF) tumor suppressor. Here, we show that p14(ARF) increases the level of p53 acetylated at lysine 382 in a nuclear chromatin-rich fraction. Unexpectedly, this accumulation of p53AcK382 is dramatically enhanced in the presence of ectopic mdm2. In light of these observations, we propose that p14(ARF) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53. Supporting this notion, we show that p53AcK382 can be deacetylated in the cytoplasm and that sirtuin SirT2 catalyzes this reaction. These results help understand why inhibition of both SirT1 and SirT2 is needed to achieve effective activation of p53 by small-molecule sirtuin inhibitors. Mol Cancer Ther; 12(4); 471-80. (C) 2013 AACR.

    Original languageEnglish
    Pages (from-to)471-480
    Number of pages10
    JournalMolecular Cancer Therapeutics
    Volume12
    Issue number4
    DOIs
    Publication statusPublished - Apr 2013

    Keywords

    • ACTIVATION
    • LOCALIZATION
    • DEACETYLATION
    • COMPLEX
    • PROTEIN
    • TUMOR-SUPPRESSOR
    • DEGRADATION
    • IN-VIVO
    • PATHWAY
    • ONCOPROTEIN MDM2

    Fingerprint

    Dive into the research topics of 'Modulation of p53 C-terminal acetylation by mdm2, p14<sup>ARF</sup>, and cytoplasmic SirT2'. Together they form a unique fingerprint.

    Cite this