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

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    Resumé

    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.
    OriginalsprogEngelsk
    TidsskriftBiochimica et Biophysica Acta - General Subjects
    Vol/bind1800
    Udgave nummer12
    Sider (fra-til)1231-1240
    ISSN0304-4165
    DOI
    StatusUdgivet - 2010

    Citer dette

    Laske, Magdalena J. ; Vogel, Ulla ; Jensen, Uffe B. ; Nexø, Bjørn A. / p53 and PPP1R13L (alias iASPP or RAI) form a feedback loop to regulate genotoxic stress responses. I: Biochimica et Biophysica Acta - General Subjects. 2010 ; Bind 1800, Nr. 12. s. 1231-1240.
    @article{c7fc6a0b86af4a888d437a6e9ef9d698,
    title = "p53 and PPP1R13L (alias iASPP or RAI) form a feedback loop to regulate genotoxic stress responses",
    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.",
    keywords = "DNA damage, p53 tumor suppressor, PPP1R13L, Apoptosis, Proteasome inhibitor",
    author = "Laske, {Magdalena J.} and Ulla Vogel and Jensen, {Uffe B.} and Nex{\o}, {Bj{\o}rn A.}",
    year = "2010",
    doi = "10.1016/j.bbagen.2010.09.002",
    language = "English",
    volume = "1800",
    pages = "1231--1240",
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    p53 and PPP1R13L (alias iASPP or RAI) form a feedback loop to regulate genotoxic stress responses. / Laske, Magdalena J.; Vogel, Ulla; Jensen, Uffe B.; Nexø, Bjørn A.

    I: Biochimica et Biophysica Acta - General Subjects, Bind 1800, Nr. 12, 2010, s. 1231-1240.

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    TY - JOUR

    T1 - p53 and PPP1R13L (alias iASPP or RAI) form a feedback loop to regulate genotoxic stress responses

    AU - Laske, Magdalena J.

    AU - Vogel, Ulla

    AU - Jensen, Uffe B.

    AU - Nexø, Bjørn A.

    PY - 2010

    Y1 - 2010

    N2 - 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.

    AB - 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.

    KW - DNA damage

    KW - p53 tumor suppressor

    KW - PPP1R13L

    KW - Apoptosis

    KW - Proteasome inhibitor

    U2 - 10.1016/j.bbagen.2010.09.002

    DO - 10.1016/j.bbagen.2010.09.002

    M3 - Journal article

    VL - 1800

    SP - 1231

    EP - 1240

    JO - B B A - General Subjects

    JF - B B A - General Subjects

    SN - 0304-4165

    IS - 12

    ER -