Involvement of MINK, a Ste20 family kinase, in Ras oncogene-induced growth arrest in human ovarian surface epithelial cells

Barbara Nicke, Julie Bastien, Sophia J. Khanna, Patricia H. Warne, Victoria Cowling, Simon J. Cook, Gordon Peters, Oona Delpuech, Almut Schulze, Katrien Berns, Jasper Mullenders, Roderick L. Beijersbergen, René Bernards, Trivadi S. Ganesan, Julian Downward, David C. Hancock

    Research output: Contribution to journalArticlepeer-review

    73 Citations (Scopus)

    Abstract

    The ability of activated Ras to induce growth arrest of human ovarian surface epithelial (HOSE) cells via induction of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 has been used to screen for Ras pathway signaling components using a library of RNA interference (RNAi) vectors targeting the kinome. Two known Ras-regulated kinases were identified, phosphoinositide 3-kinase p110a and ribosomal protein S6 kinase p70S6K1, plus the MAP kinase kinase kinase kinase MINK, which had not previously been implicated in Ras signaling. MINK is activated after Ras induction via a mechanism involving reactive oxygen species and mediates stimulation of the stress-activated protein kinase p38 MAPK downstream of the Raf/ERK pathway. p38 MAPK activation is essential for Ras-induced p21WAF1/CIP1 upregulation and cell cycle arrest. MINK is thus a distal target of Ras signaling in the induction of a growth-arrested, senescent-like phenotype that may act to oppose oncogenic transformation in HOSE cells.

    Original languageEnglish
    Pages (from-to)673-85
    Number of pages13
    JournalMolecular Cell
    Volume20
    Issue number5
    DOIs
    Publication statusPublished - 2005

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