Primary cultured neurons devoid of cellular prion display lower responsiveness to Staurosporine through the control of p53 at both transcriptional and post-transcriptional levels

Erwan Paitel, Claire Sunyach, Cristine Alves da Costa, Jean-Christophe Bourdon, Bruno Vincent, Frederic Checler

    Research output: Contribution to journalArticle

    58 Citations (Scopus)

    Abstract

    We assessed the contribution of the cellular prion protein (PrPc) in the control of neuronal apoptosis by examining cell death in both human cells and murine primary cultured neurons. We first confirmed our previous finding that staurosporine-induced caspase activation is increased by PrPc overexpression in HEK293 cells. We show here that this phenotype is fully dependent on p53 and that the control of p53 activity by PrPc occurs at both transcriptional and post-transcriptional levels in human cells. Of most interest, we demonstrate that neuronal endogenous PrPc also controls a p53-dependent pro-apoptotic phenotype. Thus, DNA fragmentation and TUNEL ( terminal deoxynucleotidyltransferase- mediated dUTP nick end-labeling)-positive cells were lower in primary cultured neurons derived from Zrch-1 mice embryos in which PrPc has been abrogated than in wildtype neurons. PrPc knock-out neurons also displayed drastically diminished caspase-3-like activity and immunoreactivity together with reduced p53 expression and transcriptional activity, a phenotype complemented in part by PrPc transfection. Interestingly, p53 expression was also reduced in the brain of adult Prnp(-/-) mice. Neuronal PrPc likely controls p53 at a post-transcriptional level because the deletion of cellular prion protein is accompanied by a higher Mdm2-like immunoreactivity and reduced phosphorylated p38 MAPK expression. We therefore propose that the physiological function of endogenous cellular prion could be to regulate p53-dependent caspase-3-mediated neuronal cell death. This phenotype likely occurs through upregulation of p53 promoter transactivation as well as downstream by controlling p53 stability via Mdm2 expression.

    Original languageEnglish
    Pages (from-to)612-618
    Number of pages7
    JournalJournal of Biological Chemistry
    Volume279
    Issue number1
    DOIs
    Publication statusPublished - 2004

    Cite this

    @article{d2ec5c9643fb4068a4ce61b38a33f7a3,
    title = "Primary cultured neurons devoid of cellular prion display lower responsiveness to Staurosporine through the control of p53 at both transcriptional and post-transcriptional levels",
    abstract = "We assessed the contribution of the cellular prion protein (PrPc) in the control of neuronal apoptosis by examining cell death in both human cells and murine primary cultured neurons. We first confirmed our previous finding that staurosporine-induced caspase activation is increased by PrPc overexpression in HEK293 cells. We show here that this phenotype is fully dependent on p53 and that the control of p53 activity by PrPc occurs at both transcriptional and post-transcriptional levels in human cells. Of most interest, we demonstrate that neuronal endogenous PrPc also controls a p53-dependent pro-apoptotic phenotype. Thus, DNA fragmentation and TUNEL ( terminal deoxynucleotidyltransferase- mediated dUTP nick end-labeling)-positive cells were lower in primary cultured neurons derived from Zrch-1 mice embryos in which PrPc has been abrogated than in wildtype neurons. PrPc knock-out neurons also displayed drastically diminished caspase-3-like activity and immunoreactivity together with reduced p53 expression and transcriptional activity, a phenotype complemented in part by PrPc transfection. Interestingly, p53 expression was also reduced in the brain of adult Prnp(-/-) mice. Neuronal PrPc likely controls p53 at a post-transcriptional level because the deletion of cellular prion protein is accompanied by a higher Mdm2-like immunoreactivity and reduced phosphorylated p38 MAPK expression. We therefore propose that the physiological function of endogenous cellular prion could be to regulate p53-dependent caspase-3-mediated neuronal cell death. This phenotype likely occurs through upregulation of p53 promoter transactivation as well as downstream by controlling p53 stability via Mdm2 expression.",
    author = "Erwan Paitel and Claire Sunyach and {da Costa}, {Cristine Alves} and Jean-Christophe Bourdon and Bruno Vincent and Frederic Checler",
    year = "2004",
    doi = "10.1074/jbc.M310453200",
    language = "English",
    volume = "279",
    pages = "612--618",
    journal = "Journal of Biological Chemistry",
    issn = "0021-9258",
    publisher = "American Society for Biochemistry and Molecular Biology",
    number = "1",

    }

    Primary cultured neurons devoid of cellular prion display lower responsiveness to Staurosporine through the control of p53 at both transcriptional and post-transcriptional levels. / Paitel, Erwan; Sunyach, Claire; da Costa, Cristine Alves; Bourdon, Jean-Christophe; Vincent, Bruno; Checler, Frederic.

    In: Journal of Biological Chemistry, Vol. 279, No. 1, 2004, p. 612-618.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Primary cultured neurons devoid of cellular prion display lower responsiveness to Staurosporine through the control of p53 at both transcriptional and post-transcriptional levels

    AU - Paitel, Erwan

    AU - Sunyach, Claire

    AU - da Costa, Cristine Alves

    AU - Bourdon, Jean-Christophe

    AU - Vincent, Bruno

    AU - Checler, Frederic

    PY - 2004

    Y1 - 2004

    N2 - We assessed the contribution of the cellular prion protein (PrPc) in the control of neuronal apoptosis by examining cell death in both human cells and murine primary cultured neurons. We first confirmed our previous finding that staurosporine-induced caspase activation is increased by PrPc overexpression in HEK293 cells. We show here that this phenotype is fully dependent on p53 and that the control of p53 activity by PrPc occurs at both transcriptional and post-transcriptional levels in human cells. Of most interest, we demonstrate that neuronal endogenous PrPc also controls a p53-dependent pro-apoptotic phenotype. Thus, DNA fragmentation and TUNEL ( terminal deoxynucleotidyltransferase- mediated dUTP nick end-labeling)-positive cells were lower in primary cultured neurons derived from Zrch-1 mice embryos in which PrPc has been abrogated than in wildtype neurons. PrPc knock-out neurons also displayed drastically diminished caspase-3-like activity and immunoreactivity together with reduced p53 expression and transcriptional activity, a phenotype complemented in part by PrPc transfection. Interestingly, p53 expression was also reduced in the brain of adult Prnp(-/-) mice. Neuronal PrPc likely controls p53 at a post-transcriptional level because the deletion of cellular prion protein is accompanied by a higher Mdm2-like immunoreactivity and reduced phosphorylated p38 MAPK expression. We therefore propose that the physiological function of endogenous cellular prion could be to regulate p53-dependent caspase-3-mediated neuronal cell death. This phenotype likely occurs through upregulation of p53 promoter transactivation as well as downstream by controlling p53 stability via Mdm2 expression.

    AB - We assessed the contribution of the cellular prion protein (PrPc) in the control of neuronal apoptosis by examining cell death in both human cells and murine primary cultured neurons. We first confirmed our previous finding that staurosporine-induced caspase activation is increased by PrPc overexpression in HEK293 cells. We show here that this phenotype is fully dependent on p53 and that the control of p53 activity by PrPc occurs at both transcriptional and post-transcriptional levels in human cells. Of most interest, we demonstrate that neuronal endogenous PrPc also controls a p53-dependent pro-apoptotic phenotype. Thus, DNA fragmentation and TUNEL ( terminal deoxynucleotidyltransferase- mediated dUTP nick end-labeling)-positive cells were lower in primary cultured neurons derived from Zrch-1 mice embryos in which PrPc has been abrogated than in wildtype neurons. PrPc knock-out neurons also displayed drastically diminished caspase-3-like activity and immunoreactivity together with reduced p53 expression and transcriptional activity, a phenotype complemented in part by PrPc transfection. Interestingly, p53 expression was also reduced in the brain of adult Prnp(-/-) mice. Neuronal PrPc likely controls p53 at a post-transcriptional level because the deletion of cellular prion protein is accompanied by a higher Mdm2-like immunoreactivity and reduced phosphorylated p38 MAPK expression. We therefore propose that the physiological function of endogenous cellular prion could be to regulate p53-dependent caspase-3-mediated neuronal cell death. This phenotype likely occurs through upregulation of p53 promoter transactivation as well as downstream by controlling p53 stability via Mdm2 expression.

    U2 - 10.1074/jbc.M310453200

    DO - 10.1074/jbc.M310453200

    M3 - Article

    VL - 279

    SP - 612

    EP - 618

    JO - Journal of Biological Chemistry

    JF - Journal of Biological Chemistry

    SN - 0021-9258

    IS - 1

    ER -