A novel role for mixed-lineage kinase-like mitogen-activated protein triple kinase alpha in neoplastic cell transformation and tumor development.

Abstract

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.

• Authors: Yong-Yeon Cho, Ann M Bode, Hideya Mizuno, Bu Young Choi, Hong Seok Choi, Zigang Dong
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 11 Pg. 3855-64 (Jun 01 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15172994 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carcinogens
• RNA, Small Interfering
• Transcription Factors
• Epidermal Growth Factor
• MAP Kinase Kinase Kinases
• MLK-like mitogen-activated protein triple kinase
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Base Sequence
• Carcinogens (pharmacology)
• Cell Adhesion (physiology)
• Cell Division (physiology)
• Cell Transformation, Neoplastic (metabolism)
• Cells, Cultured
• Epidermal Growth Factor (pharmacology)
• MAP Kinase Kinase Kinases (biosynthesis, genetics)
• MAP Kinase Signaling System (drug effects, physiology)
• Mice
• Mice, Nude
• Molecular Sequence Data
• Phosphorylation
• RNA, Small Interfering (genetics)
• Skin (cytology, drug effects, enzymology)
• Skin Neoplasms (chemically induced, enzymology, genetics)
• Tetradecanoylphorbol Acetate (pharmacology)
• Transcription Factors (genetics, metabolism)