Involvement of MINK, a Ste20 Family Kinase, in Ras Oncogene-Induced Growth Arrest in Human Ovarian Surface Epithelial Cells

Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Molecular Cell (Impact Factor: 14.02). 01/2006; 20(5):673-85. DOI: 10.1016/j.molcel.2005.10.038
Source: PubMed


The ability of activated Ras to induce growth arrest of human ovarian surface epithelial (HOSE) cells via induction of the cyclin-dependent kinase inhibitor p21(WAF1/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 p110alpha and ribosomal protein S6 kinase p70(S6K1), 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 p21(WAF1/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.

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    • "The role of Mink1 in cancer has been recently studied [32]. Interestingly, previous reports have shown that oncogenic KRas activity causes increased MINK1 activity and expression [33], and that MAP4K4 expression is heightened in tumor cell lines and tumor tissues compared with their normal counterparts [34], [35]. Those reports suggested the interesting possibility that Msn kinases (which include MINK1) might be involved in inhibiting the tumor-suppressing functions of TGF-β/BMP in various cancers. "
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    • "Msn belongs to the HPK/GCK family kinases, a family that encompasses eight subfamilies. The GCK-IV subfamily, or Msn subfamily, includes NIK/HGK (Nck-interacting kinase/HPK/GCK-like kinase) [20], [21], [22], [23], [24], TNIK (Traf2 and Nck-interacting kinase) [25], [26], MINK (Misshapen/NIKs-related kinase) [27], [28], [29], and NRK/NESK (NIK-related kinase/NIK-like embryo-specific kinase) [30], [31] as well as Drosophila Msn [32], [33], [34], [35], [36] and the C. elegans ortholog Mig-15 [37]. All of the Msn kinases have been shown to activate JNK [22], [34]. "
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    • "To explore the mechanism of Ras-initiated cell death, we used a tetracycline-inducible H-Ras V12 human ovarian surface epithelial (HOSE) cell line, previously characterized by Hancock and colleagues (Nicke et al., 2005). Upon induction of Ras V12 expression , HOSE cells undergo irreversible proliferative arrest and display a marked reduction in the ability to form colonies (Nicke et al., 2005). Using this system, we have found that induction of H-Ras V12 expression induced cell death, which was associated with a strong upregulation of Noxa—a member of the BH3- only subset of the Bcl-2 family. "
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