Proenkephalin assists stress-activated apoptosis through transcriptional repression of NF-B- and p53-regulated gene targets

N. McTavish, L. A. Copeland, M. K. Saville, N. D. Perkins, B. A. Spruce

    Research output: Contribution to journalArticle

    23 Citations (Scopus)

    Abstract

    NOTE: THE SPECIAL CHARACTERS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY. PLEASE REFER TO THE THE PUBLISHER'S WEBSITE FOR AN ACCURATE DISPLAY. The respective pro- and antiapoptotic functions of the transcription factors p53 and nuclear factor jB (NF-jB), and their potential impact on tumorigenesis and response to tumor therapy are well recognized. The capacity of the RelA(p65) subunit of NF-jB to specify a pro-apoptotic outcome in response to some stimuli is less well recognized, but needs to be understood if rational manipulation of the NF-jB pathway is to be deployed in cancer therapy. In this report, we provide evidence that the growth responsive nuclear protein, proenkephalin (Penk), is required, in part, for apoptosis induction, in response to activation ooverexpression of p53 and RelA(p65). We describe UV-C-inducible physical associations between endogenous Penk and p53 and RelA(p65) in mammalian cell lines. Depletion of Penk by RNA interference (RNAi) substantially preserves viable cell number following exposure to UV-C irradiation or hydrogen peroxide and confers transient protection in cells exposed to the genotoxin etoposide. In virally transformed and human tumor cell lines, overexpression of nuclear Penk with overabundant or activated p53, or RelA(p65) even in the absence of p53, enhances apoptosis to the point of synergy. We have further shown that Penk depletion by RNAi substantially derepresses transcription of a range of antiapoptotic gene targets previously implicated in repression-mediated apoptosis induction by NF-jB and p53. Physical association of endogenous Penk with the transcriptional co-repressor histone deacetylase suggests that it may be a component of a transcriptional repression complex that contributes to a pro-apoptotic outcome, following activation of the NF-jB and p53 pathways, and could therefore help to facilitate an antitumor response to a broad range of agents.
    Original languageEnglish
    Pages (from-to)1700-1710
    Number of pages11
    JournalCell Death & Differentiation
    Volume14
    Issue number9
    DOIs
    Publication statusPublished - 2007

    Fingerprint

    p53 Genes
    Apoptosis
    RNA Interference
    Co-Repressor Proteins
    Histone Deacetylases
    Cytoprotection
    Mutagens
    Etoposide
    Nuclear Proteins
    Tumor Cell Line
    Hydrogen Peroxide
    proenkephalin
    Neoplasms
    Carcinogenesis
    Transcription Factors
    Cell Count
    Cell Line
    Therapeutics
    Growth
    Genes

    Keywords

    • Apoptosis
    • NF-kappa B
    • Proenkephalin

    Cite this

    McTavish, N. ; Copeland, L. A. ; Saville, M. K. ; Perkins, N. D. ; Spruce, B. A. / Proenkephalin assists stress-activated apoptosis through transcriptional repression of NF-B- and p53-regulated gene targets. In: Cell Death & Differentiation. 2007 ; Vol. 14, No. 9. pp. 1700-1710.
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    abstract = "NOTE: THE SPECIAL CHARACTERS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY. PLEASE REFER TO THE THE PUBLISHER'S WEBSITE FOR AN ACCURATE DISPLAY. The respective pro- and antiapoptotic functions of the transcription factors p53 and nuclear factor jB (NF-jB), and their potential impact on tumorigenesis and response to tumor therapy are well recognized. The capacity of the RelA(p65) subunit of NF-jB to specify a pro-apoptotic outcome in response to some stimuli is less well recognized, but needs to be understood if rational manipulation of the NF-jB pathway is to be deployed in cancer therapy. In this report, we provide evidence that the growth responsive nuclear protein, proenkephalin (Penk), is required, in part, for apoptosis induction, in response to activation ooverexpression of p53 and RelA(p65). We describe UV-C-inducible physical associations between endogenous Penk and p53 and RelA(p65) in mammalian cell lines. Depletion of Penk by RNA interference (RNAi) substantially preserves viable cell number following exposure to UV-C irradiation or hydrogen peroxide and confers transient protection in cells exposed to the genotoxin etoposide. In virally transformed and human tumor cell lines, overexpression of nuclear Penk with overabundant or activated p53, or RelA(p65) even in the absence of p53, enhances apoptosis to the point of synergy. We have further shown that Penk depletion by RNAi substantially derepresses transcription of a range of antiapoptotic gene targets previously implicated in repression-mediated apoptosis induction by NF-jB and p53. Physical association of endogenous Penk with the transcriptional co-repressor histone deacetylase suggests that it may be a component of a transcriptional repression complex that contributes to a pro-apoptotic outcome, following activation of the NF-jB and p53 pathways, and could therefore help to facilitate an antitumor response to a broad range of agents.",
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    Proenkephalin assists stress-activated apoptosis through transcriptional repression of NF-B- and p53-regulated gene targets. / McTavish, N.; Copeland, L. A.; Saville, M. K.; Perkins, N. D.; Spruce, B. A.

    In: Cell Death & Differentiation, Vol. 14, No. 9, 2007, p. 1700-1710.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Proenkephalin assists stress-activated apoptosis through transcriptional repression of NF-B- and p53-regulated gene targets

    AU - McTavish, N.

    AU - Copeland, L. A.

    AU - Saville, M. K.

    AU - Perkins, N. D.

    AU - Spruce, B. A.

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    N2 - NOTE: THE SPECIAL CHARACTERS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY. PLEASE REFER TO THE THE PUBLISHER'S WEBSITE FOR AN ACCURATE DISPLAY. The respective pro- and antiapoptotic functions of the transcription factors p53 and nuclear factor jB (NF-jB), and their potential impact on tumorigenesis and response to tumor therapy are well recognized. The capacity of the RelA(p65) subunit of NF-jB to specify a pro-apoptotic outcome in response to some stimuli is less well recognized, but needs to be understood if rational manipulation of the NF-jB pathway is to be deployed in cancer therapy. In this report, we provide evidence that the growth responsive nuclear protein, proenkephalin (Penk), is required, in part, for apoptosis induction, in response to activation ooverexpression of p53 and RelA(p65). We describe UV-C-inducible physical associations between endogenous Penk and p53 and RelA(p65) in mammalian cell lines. Depletion of Penk by RNA interference (RNAi) substantially preserves viable cell number following exposure to UV-C irradiation or hydrogen peroxide and confers transient protection in cells exposed to the genotoxin etoposide. In virally transformed and human tumor cell lines, overexpression of nuclear Penk with overabundant or activated p53, or RelA(p65) even in the absence of p53, enhances apoptosis to the point of synergy. We have further shown that Penk depletion by RNAi substantially derepresses transcription of a range of antiapoptotic gene targets previously implicated in repression-mediated apoptosis induction by NF-jB and p53. Physical association of endogenous Penk with the transcriptional co-repressor histone deacetylase suggests that it may be a component of a transcriptional repression complex that contributes to a pro-apoptotic outcome, following activation of the NF-jB and p53 pathways, and could therefore help to facilitate an antitumor response to a broad range of agents.

    AB - NOTE: THE SPECIAL CHARACTERS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY. PLEASE REFER TO THE THE PUBLISHER'S WEBSITE FOR AN ACCURATE DISPLAY. The respective pro- and antiapoptotic functions of the transcription factors p53 and nuclear factor jB (NF-jB), and their potential impact on tumorigenesis and response to tumor therapy are well recognized. The capacity of the RelA(p65) subunit of NF-jB to specify a pro-apoptotic outcome in response to some stimuli is less well recognized, but needs to be understood if rational manipulation of the NF-jB pathway is to be deployed in cancer therapy. In this report, we provide evidence that the growth responsive nuclear protein, proenkephalin (Penk), is required, in part, for apoptosis induction, in response to activation ooverexpression of p53 and RelA(p65). We describe UV-C-inducible physical associations between endogenous Penk and p53 and RelA(p65) in mammalian cell lines. Depletion of Penk by RNA interference (RNAi) substantially preserves viable cell number following exposure to UV-C irradiation or hydrogen peroxide and confers transient protection in cells exposed to the genotoxin etoposide. In virally transformed and human tumor cell lines, overexpression of nuclear Penk with overabundant or activated p53, or RelA(p65) even in the absence of p53, enhances apoptosis to the point of synergy. We have further shown that Penk depletion by RNAi substantially derepresses transcription of a range of antiapoptotic gene targets previously implicated in repression-mediated apoptosis induction by NF-jB and p53. Physical association of endogenous Penk with the transcriptional co-repressor histone deacetylase suggests that it may be a component of a transcriptional repression complex that contributes to a pro-apoptotic outcome, following activation of the NF-jB and p53 pathways, and could therefore help to facilitate an antitumor response to a broad range of agents.

    KW - Apoptosis

    KW - NF-kappa B

    KW - Proenkephalin

    U2 - 10.1038/sj.cdd.4402172

    DO - 10.1038/sj.cdd.4402172

    M3 - Article

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    EP - 1710

    JO - Cell Death & Differentiation

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