p53 and PPP1R13L (alias iASPP or RAI) form a feedback loop to regulate genotoxic stress responses

Magdalena J. Laske, Ulla Vogel, Uffe B. Jensen, Bjørn A. Nexø

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    Background: PPP1R13L gene has been found to be over-expressed in variety of cancers and its expression in
    p53 wild-type background is sufficient to promote tumor growth in vivo. However, in the non-transformed
    cells it acts as a tumor suppressor which suggests that the role of PPP1R13L is multifaceted.
    Methods: We have used siRNA optimized for inhibition of p53, PPP1R13L, BAX and GADD45 alpha expression
    and investigated the role of those gene products for PPP1R13L expression and induction in a variety of mouse
    and human cells with different p53 status. In addition we have applied Western Blot, Q-PCR and proteasome
    inhibition analysis to further ascertain the link between PPP1R13L induction and p53 status.
    Results: We show that the pattern and extent of the PPP1R13L expression depend on the presence of active
    p53. Downregulation of p53 target genes BAX and/or GADD45 alpha led to decreased in PPP1R13L activation
    after adriamycin and/or etoposide treatments. Treatment of the cells with the proteasome inhibitor MG-132
    resulted in the accumulation of both p53 and PPP1R13L proteins.
    Conclusions: We have provided evidence that endogenous PPP1R13L acts as a negative regulator of p53
    function, presumably by direct binding. p53 accumulation and activity after DNA damage is compromised by
    PPP1R13L expression. We suggest that PPP1R13L and p53 form a negative feedback loop which regulates their
    amount and activity.
    General significance: The profound modulatory effect of the PPP1R13L protein on the ability of p53 to cause
    cellular apoptosis has important implications in cancer and presents new therapeutic possibilities.
    Original languageEnglish
    JournalBiochimica et Biophysica Acta - General Subjects
    Volume1800
    Issue number12
    Pages (from-to)1231-1240
    ISSN0304-4165
    DOIs
    Publication statusPublished - 2010

    Keywords

    • DNA damage
    • p53 tumor suppressor
    • PPP1R13L
    • Apoptosis
    • Proteasome inhibitor

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