| RRC ID |
38150
|
| 著者 |
Shitashige M, Satow R, Jigami T, Aoki K, Honda K, Shibata T, Ono M, Hirohashi S, Yamada T.
|
| タイトル |
Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth.
|
| ジャーナル |
Cancer Res
|
| Abstract |
T-cell factor-4 (TCF4) is a transcription factor essential for maintaining the undifferentiated status and self-renewal of intestinal epithelial cells. It has therefore been considered that constitutive activation of TCF4 by aberrant Wnt signaling is a major force driving colorectal carcinogenesis. We previously identified Traf2- and Nck-interacting kinase (TNIK) as one of the proteins that interact with TCF4 in colorectal cancer cells, but its functional significance has not been elucidated. Here, we report that TNIK is an activating kinase for TCF4 and essential for colorectal cancer growth. TNIK, but not its catalytically inactive mutant, phosphorylated the conserved serine 154 residue of TCF4. Small interfering RNA targeting TNIK inhibited the proliferation of colorectal cancer cells and the growth of tumors produced by injecting colorectal cancer cells s.c. into immunodeficient mice. The growth inhibition was abolished by restoring the catalytic domain of TNIK, thus confirming that its enzyme activity is essential for the maintenance of colorectal cancer growth. Several ATP-competing kinase inhibitors have been applied to cancer treatment and have shown significant activity. Our findings suggest TNIK as a feasible target for pharmacologic intervention to ablate aberrant Wnt signaling in colorectal cancer.
|
| 巻・号 |
70(12)
|
| ページ |
5024-33
|
| 公開日 |
2010-6-15
|
| DOI |
10.1158/0008-5472.CAN-10-0306
|
| PII |
0008-5472.CAN-10-0306
|
| PMID |
20530691
|
| MeSH |
Adenoviridae / genetics
Animals
Blotting, Western
Cell Proliferation
Chromatography, Liquid
Colony-Forming Units Assay
Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism*
Colorectal Neoplasms / pathology*
Female
Germinal Center Kinases
Humans
Immunoblotting
Immunoenzyme Techniques
Immunoprecipitation
Luciferases / metabolism
Mass Spectrometry
Mice
Mice, Inbred BALB C
Mice, Nude
Phosphorylation
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Small Interfering / pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
TNF Receptor-Associated Factor 2 / genetics
TNF Receptor-Associated Factor 2 / metabolism*
Tumor Cells, Cultured
Two-Hybrid System Techniques
Wnt Proteins / genetics
Wnt Proteins / metabolism*
beta Catenin / genetics
beta Catenin / metabolism
|
| IF |
9.727
|
| 引用数 |
67
|
|
WOS 分野
|
ONCOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
|
