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A Novel Role for Mixed-Lineage Kinase-Like Mitogen-Activated Protein Triple Kinase in Neoplastic Cell Transformation and Tumor Development

Hormel Institute University of Minnesota, Austin, Minnesota

Previously, no member of the mixed-lineage kinase (MLK) protein family was known to function as an oncogene. Here, we demonstrate that MLK-like mitogen-activated protein triple kinase (MLTK)-, a member of the MLK family, induced neoplastic cell transformation and tumorigenesis in athymic nude mice. Introduction of small interference RNA (siRNA)-MLTK- into MLTK--overexpressing cells dramatically suppressed cell transformation. Nuclear accumulation of the pHisG-MLTK- fusion protein was observed after epidermal growth factor or 12-O-tetradecanoylphorbol-13-acetate treatment. Phosphorylation of downstream mitogen-activated protein kinase-targeted transcription factors including c-Myc, Elk-1, c-Jun, and activating transcription factor (ATF) 2 was also differentially enhanced in MLTK--overexpressing cells exposed to epidermal growth factor or 12-O-tetradecanoylphorbol-13-acetate stimulation compared with cells expressing mock vector or siRNA-MLTK-. Very importantly, MLTK--overexpressing cells formed fibrosarcomas when injected s.c. into athymic nude mice, whereas almost no tumor formation was observed in mice that received injections of mock or siRNA-MLTK- stably transfected cells. These results are the first to indicate that MLTK- plays a key role in neoplastic cell transformation and cancer development.

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