ERK/p90(RSK)/14-3-3 signalling has an impact on expression of PEA3 Ets transcription factors via the transcriptional repressor capicua

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    Abstract

    Compounds that inhibit signalling upstream of ERK (extracellular-signal-regulated kinase) are promising anticancer therapies, motivating research to define how this pathway promotes cancers. In the present study, we show that human capicua represses mRNA expression for PEA3 (polyoma enhancer activator 3) Ets transcription factors ETV1, ETV4 and ETV5 (ETV is Ets translocation variant), and this repression is relieved by multisite controls of capicua by ERK, p90(RSK) (p90 ribosomal S6 kinase) and 14-3-3 proteins. Specifically, 14-3-3 binds to p90(RSK)-phosphorylated Ser(173) of capicua thereby modulating DNA binding to its HMG (high-mobility group) box, whereas ERK phosphorylations prevent binding of a C-terminal NLS (nuclear localization sequence) to importin alpha 4 (KPNA3). ETV1. ETV4 and ETV5 mRNA levels in melanoma cells are elevated by siRNA (small interfering RNA) knockdown of capicua, and decreased by inhibiting ERK and/or expressing a form of capicua that cannot bind to 14-3-3 proteins. Capicua knockdown also enhances cell migration. The findings of the present study give further mechanistic insights into why ETV1 is highly expressed in certain cancers, indicate that loss of capicua can desensitize cells to the effects of ERK pathway inhibitors, and highlight interconnections among growth factor signalling, spinocerebellar ataxias and cancers.

    Original languageEnglish
    Pages (from-to)515-525
    Number of pages11
    JournalBiochemical Journal
    Volume433
    DOIs
    Publication statusPublished - 1 Feb 2011

    Keywords

    • cancer
    • capicua
    • Ets translocation variant 1 (ETV 1)
    • 14-3-3 protein
    • spinocerebellar ataxia type 1 (SCA 1)
    • PROTEIN-KINASE INHIBITORS
    • PROSTATE-CANCER
    • GENE
    • ETV1
    • ATAXIN-1
    • SCA1
    • IDENTIFICATION
    • TRANSLOCATION
    • MELANOMA
    • NEURONS

    Cite this

    @article{aec9523b82a544328a03102ced0c778e,
    title = "ERK/p90(RSK)/14-3-3 signalling has an impact on expression of PEA3 Ets transcription factors via the transcriptional repressor capicua",
    abstract = "Compounds that inhibit signalling upstream of ERK (extracellular-signal-regulated kinase) are promising anticancer therapies, motivating research to define how this pathway promotes cancers. In the present study, we show that human capicua represses mRNA expression for PEA3 (polyoma enhancer activator 3) Ets transcription factors ETV1, ETV4 and ETV5 (ETV is Ets translocation variant), and this repression is relieved by multisite controls of capicua by ERK, p90(RSK) (p90 ribosomal S6 kinase) and 14-3-3 proteins. Specifically, 14-3-3 binds to p90(RSK)-phosphorylated Ser(173) of capicua thereby modulating DNA binding to its HMG (high-mobility group) box, whereas ERK phosphorylations prevent binding of a C-terminal NLS (nuclear localization sequence) to importin alpha 4 (KPNA3). ETV1. ETV4 and ETV5 mRNA levels in melanoma cells are elevated by siRNA (small interfering RNA) knockdown of capicua, and decreased by inhibiting ERK and/or expressing a form of capicua that cannot bind to 14-3-3 proteins. Capicua knockdown also enhances cell migration. The findings of the present study give further mechanistic insights into why ETV1 is highly expressed in certain cancers, indicate that loss of capicua can desensitize cells to the effects of ERK pathway inhibitors, and highlight interconnections among growth factor signalling, spinocerebellar ataxias and cancers.",
    keywords = "cancer, capicua, Ets translocation variant 1 (ETV 1), 14-3-3 protein, spinocerebellar ataxia type 1 (SCA 1), PROTEIN-KINASE INHIBITORS, PROSTATE-CANCER, GENE, ETV1, ATAXIN-1, SCA1, IDENTIFICATION, TRANSLOCATION, MELANOMA, NEURONS",
    author = "Kumara Dissanayake and Rachel Toth and Jamie Blakey and Olof Olsson and Campbell, {David G.} and Prescott, {Alan R.} and Carol MacKintosh",
    year = "2011",
    month = "2",
    day = "1",
    doi = "10.1042/BJ20101562",
    language = "English",
    volume = "433",
    pages = "515--525",
    journal = "Biochemical Journal",
    issn = "0264-6021",
    publisher = "Portland Press",

    }

    TY - JOUR

    T1 - ERK/p90(RSK)/14-3-3 signalling has an impact on expression of PEA3 Ets transcription factors via the transcriptional repressor capicua

    AU - Dissanayake, Kumara

    AU - Toth, Rachel

    AU - Blakey, Jamie

    AU - Olsson, Olof

    AU - Campbell, David G.

    AU - Prescott, Alan R.

    AU - MacKintosh, Carol

    PY - 2011/2/1

    Y1 - 2011/2/1

    N2 - Compounds that inhibit signalling upstream of ERK (extracellular-signal-regulated kinase) are promising anticancer therapies, motivating research to define how this pathway promotes cancers. In the present study, we show that human capicua represses mRNA expression for PEA3 (polyoma enhancer activator 3) Ets transcription factors ETV1, ETV4 and ETV5 (ETV is Ets translocation variant), and this repression is relieved by multisite controls of capicua by ERK, p90(RSK) (p90 ribosomal S6 kinase) and 14-3-3 proteins. Specifically, 14-3-3 binds to p90(RSK)-phosphorylated Ser(173) of capicua thereby modulating DNA binding to its HMG (high-mobility group) box, whereas ERK phosphorylations prevent binding of a C-terminal NLS (nuclear localization sequence) to importin alpha 4 (KPNA3). ETV1. ETV4 and ETV5 mRNA levels in melanoma cells are elevated by siRNA (small interfering RNA) knockdown of capicua, and decreased by inhibiting ERK and/or expressing a form of capicua that cannot bind to 14-3-3 proteins. Capicua knockdown also enhances cell migration. The findings of the present study give further mechanistic insights into why ETV1 is highly expressed in certain cancers, indicate that loss of capicua can desensitize cells to the effects of ERK pathway inhibitors, and highlight interconnections among growth factor signalling, spinocerebellar ataxias and cancers.

    AB - Compounds that inhibit signalling upstream of ERK (extracellular-signal-regulated kinase) are promising anticancer therapies, motivating research to define how this pathway promotes cancers. In the present study, we show that human capicua represses mRNA expression for PEA3 (polyoma enhancer activator 3) Ets transcription factors ETV1, ETV4 and ETV5 (ETV is Ets translocation variant), and this repression is relieved by multisite controls of capicua by ERK, p90(RSK) (p90 ribosomal S6 kinase) and 14-3-3 proteins. Specifically, 14-3-3 binds to p90(RSK)-phosphorylated Ser(173) of capicua thereby modulating DNA binding to its HMG (high-mobility group) box, whereas ERK phosphorylations prevent binding of a C-terminal NLS (nuclear localization sequence) to importin alpha 4 (KPNA3). ETV1. ETV4 and ETV5 mRNA levels in melanoma cells are elevated by siRNA (small interfering RNA) knockdown of capicua, and decreased by inhibiting ERK and/or expressing a form of capicua that cannot bind to 14-3-3 proteins. Capicua knockdown also enhances cell migration. The findings of the present study give further mechanistic insights into why ETV1 is highly expressed in certain cancers, indicate that loss of capicua can desensitize cells to the effects of ERK pathway inhibitors, and highlight interconnections among growth factor signalling, spinocerebellar ataxias and cancers.

    KW - cancer

    KW - capicua

    KW - Ets translocation variant 1 (ETV 1)

    KW - 14-3-3 protein

    KW - spinocerebellar ataxia type 1 (SCA 1)

    KW - PROTEIN-KINASE INHIBITORS

    KW - PROSTATE-CANCER

    KW - GENE

    KW - ETV1

    KW - ATAXIN-1

    KW - SCA1

    KW - IDENTIFICATION

    KW - TRANSLOCATION

    KW - MELANOMA

    KW - NEURONS

    U2 - 10.1042/BJ20101562

    DO - 10.1042/BJ20101562

    M3 - Article

    VL - 433

    SP - 515

    EP - 525

    JO - Biochemical Journal

    JF - Biochemical Journal

    SN - 0264-6021

    ER -