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: 14.46). 01/2006; 20(5):673-85. DOI: 10.1016/j.molcel.2005.10.038
Source: PubMed

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 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.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: The striatin family of proteins, comprising STRN, STRN3, and STRN4, are multidomain–containing proteins that associate with additional proteins to form a large protein complex. We previously reported that STRN4 directly associated with protein kinases, such as MINK1, TNIK and MAP4K4, which are associated with tumor suppression or tumor progression. However, it remains unclear whether STRN4 is associated with tumor progression. In this report, we examined the role that STRN4 plays in cancer malignancy. We show that depletion of STRN4 suppresses proliferation, migration, invasion and the anchorage-independent growth of cancer cells. Additionally, STRN4 knockdown increased the sensitivity of pancreatic cancer cells to gemcitabine. Finally, we show that STRN4 knockdown suppressed the proliferation and metastasis of cancer cells in mice. Our results demonstrate a possible role of STRN4 in tumor progression.This article is protected by copyright. All rights reserved.
    Cancer Science 09/2014; 105(12). DOI:10.1111/cas.12541 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Colorectal cancer (CRC) remains one of the most common malignancies in the world. Although surgical resection combined with adjuvant therapy is effective at the early stages of the disease, resistance to conventional therapies is frequently observed in advanced stages, where treatments become ineffective. Resistance to cisplatin, irinotecan and 5-fluorouracil chemotherapy has been shown to involve mitogen-activated protein kinase (MAPK) signaling and recent studies identified p38α MAPK as a mediator of resistance to various agents in CRC patients. Studies published in the last decade showed a dual role for the p38α pathway in mammals. Its role as a negative regulator of proliferation has been reported in both normal (including cardiomyocytes, hepatocytes, fibroblasts, hematopoietic and lung cells) and cancer cells (colon, prostate, breast, lung tumor cells). This function is mediated by the negative regulation of cell cycle progression and the transduction of some apoptotic stimuli. However, despite its anti-proliferative and tumor suppressor activity in some tissues, the p38α pathway may also acquire an oncogenic role involving cancer related-processes such as cell metabolism, invasion, inflammation and angiogenesis. In this review, we summarize current knowledge about the predominant role of the p38α MAPK pathway in CRC development and chemoresistance. In our view, this might help establish the therapeutic potential of the targeted manipulation of this pathway in clinical settings.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human Enterovirus 71 (EV71) commonly causes Hand, Foot and Mouth Disease in young children, and occasional occurrences of neurological complications can be fatal. In this study, a high-throughput cell-based screening on the serine/threonine kinase siRNA library was performed to identify potential antiviral agents against EV71 replication. Among the hits, Misshapen/NIKs-related kinase (MINK) was selected for detailed analysis due to its strong inhibitory profile and novelty. In the investigation of the stage at which MINK is involved in EV71 replication, virus RNA transfection in MINK siRNA-treated cells continued to cause virus inhibition despite bypassing the normal entry pathway, suggesting its involvement at the post-entry stage. We have also shown that viral RNA and protein expression level was significantly reduced upon MINK silencing, suggesting its involvement in viral protein synthesis which feeds into viral RNA replication process. Through proteomic analysis and infection inhibition assay, we found that the activation of MINK was triggered by early replication events, instead of the binding and entry of the virus. Proteomic analysis on the activation profile of p38 Mitogen-activated Protein Kinase (MAPK) indicated that the phosphorylation of p38 MAPK was stimulated by EV71 infection upon MINK activation. Luciferase reporter assay further revealed that the translation efficiency of the EV71 internal ribosomal entry site (IRES) was reduced after blocking the MINK/p38 MAPK pathway. Further investigation on the effect of MINK silencing on heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) localisation demonstrated that cytoplasmic relocalisation of hnRNP A1 upon EV71 infection may be facilitated via the MINK/p38 MAPK pathway which then positively regulates the translation of viral RNA transcripts. These novel findings hence suggest that MINK plays a functional role in the IRES-mediated translation of EV71 viral RNA and may provide a potential target for the development of specific antiviral strategies against EV71 infection.
    PLoS Pathogens 02/2015; 11(3):e1004686. DOI:10.1371/journal.ppat.1004686 · 8.06 Impact Factor

Full-text (2 Sources)

Available from
May 30, 2014