A novel role for mixed-lineage kinase-like mitogen-activated protein triple kinase alpha in neoplastic cell transformation and tumor development.
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)-alpha, a member of the MLK family, induced neoplastic cell transformation and tumorigenesis in athymic nude mice. Introduction of small interference RNA (siRNA)-MLTK-alpha into MLTK-alpha-overexpressing cells dramatically suppressed cell transformation. Nuclear accumulation of the pHisG-MLTK-alpha 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-alpha-overexpressing cells exposed to epidermal growth factor or 12-O-tetradecanoylphorbol-13-acetate stimulation compared with cells expressing mock vector or siRNA-MLTK-alpha. Very importantly, MLTK-alpha-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-alpha stably transfected cells. These results are the first to indicate that MLTK-alpha plays a key role in neoplastic cell transformation and cancer development.
Cho
Yong-Yeon
YY
Hormel Institute University of Minnesota, Austin, Minnesota 55912, USA.
Bode
Ann M
AM
Mizuno
Hideya
H
Choi
Bu Young
BY
Choi
Hong Seok
HS
Dong
Zigang
Z
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D002273:Carcinogens; D034741:RNA, Small Interfering; D014157:Transcription Factors; D004815:Epidermal Growth Factor; D020930:MAP Kinase Kinase Kinases; C428384:MLK-like mitogen-activated protein triple kinase; D013755:Tetradecanoylphorbol Acetate