TY - JOUR
T1 - A novel role for mixed-lineage kinase-like mitogen-activated protein triple kinase α in neoplastic cell transformation and tumor development
AU - Cho, Yong Yeon
AU - Bode, Ann M.
AU - Mizuno, Hideya
AU - Choi, Bu Young
AU - Choi, Hong Seok
AU - Dong, Zigang
PY - 2004/6/1
Y1 - 2004/6/1
N2 - 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)-α, a member of the MLK family, induced neoplastic cell transformation and tumorigenesis in athymic nude mice. Introduction of small interference RNA (siRNA)-MLTK-α into MLTK-α-overexpressing cells dramatically suppressed cell transformation. Nuclear accumulation of the pHisG-MLTK-α 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-α-overexpressing cells exposed to epidermal growth factor or 12-O-tetradecanoylphorbol-13-acetate stimulation compared with cells expressing mock vector or siRNA-MLTK-α. Very importantly, MLTK-α -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-α stably transfected cells. These results are the first to indicate that MLTK-α plays a key role in neoplastic cell transformation and cancer development.
AB - 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)-α, a member of the MLK family, induced neoplastic cell transformation and tumorigenesis in athymic nude mice. Introduction of small interference RNA (siRNA)-MLTK-α into MLTK-α-overexpressing cells dramatically suppressed cell transformation. Nuclear accumulation of the pHisG-MLTK-α 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-α-overexpressing cells exposed to epidermal growth factor or 12-O-tetradecanoylphorbol-13-acetate stimulation compared with cells expressing mock vector or siRNA-MLTK-α. Very importantly, MLTK-α -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-α stably transfected cells. These results are the first to indicate that MLTK-α plays a key role in neoplastic cell transformation and cancer development.
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U2 - 10.1158/0008-5472.CAN-04-0201
DO - 10.1158/0008-5472.CAN-04-0201
M3 - Article
C2 - 15172994
AN - SCOPUS:2542628098
VL - 64
SP - 3855
EP - 3864
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 11
ER -