Mechanism-specific signatures for small-molecule p53 activators

Ingeborg M. M. van Leeuwen, Maureen Higgins, Johanna Campbell, Christopher J. Brown, Anna R. McCarthy, Lisa Pirrie, Nicholas J. Westwood, Sonia Lain

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    39 Citations (Scopus)

    Abstract

    Recent advances in the field of pharmacological activation of the p53 tumor suppressor are beginning to be translated into the clinic. In addition, small molecules that activate p53 through established mechanisms of action are proving invaluable tools for basic research. Here we analyze and compare the effects of nutlin-3, tenovin-6 and low doses of actinomycin-D on p53 and its main negative regulator, mdm2. We reveal striking differences in the speed at which these compounds increase p53 protein levels, with nutlin-3 having a substantial impact within minutes. We also show that nutlin-3 is very effective at increasing the synthesis of mdm2 mRNA, mdm2 being not only a modulator of p53 but also a transcriptional target. In addition, we show that nutlin-3 stabilises mdm2's conformation and protects mdm2 from degradation. These strong effects of nutlin-3 on mdm2 correlate with a remarkable rate of recovery of p53 levels upon removal of the compound. We discuss the potential application of our results as molecular signatures to assess the on-target effects of small-molecule mdm2 inhibitors. To conclude, we discuss the implications of our observations for using small-molecule p53 activators to reduce the growth of tumors retaining wild-type p53 or to protect normal tissues against the undesired side effects of conventional chemotherapy.

    Original languageEnglish
    Pages (from-to)1590-1598
    Number of pages9
    JournalCell Cycle
    Volume10
    Issue number10
    DOIs
    Publication statusPublished - 15 May 2011

    Keywords

    • p53
    • mdm2
    • nutlin-3
    • actinomycin-D
    • tenovin-6
    • RIBOSOMAL-PROTEIN L11
    • IN-VIVO
    • IMMUNOCHEMICAL ANALYSIS
    • ONCOPROTEIN MDM2
    • LIGASE ACTIVITY
    • DNA-DAMAGE
    • S-PHASE
    • CELLS
    • CANCER
    • PATHWAY

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