| RRC ID |
1376
|
| 著者 |
Ikenoue T, Hikiba Y, Kanai F, Aragaki J, Tanaka Y, Imamura J, Imamura T, Ohta M, Ijichi H, Tateishi K, Kawakami T, Matsumura M, Kawabe T, Omata M.
|
| タイトル |
Different effects of point mutations within the B-Raf glycine-rich loop in colorectal tumors on mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase and nuclear factor kappaB pathway and cellular transformation.
|
| ジャーナル |
Cancer Res
|
| Abstract |
Recently, mutations in the B-Raf gene have been identified in a variety of human cancers, such as melanoma and colorectal carcinoma, and more than 80% of the B-Raf mutations have been V599E. Although other mutations have been reported, their functional consequences are poorly understood. In our earlier study, we demonstrated that colon tumor-associated B-Raf mutations within the kinase activation segment are not necessarily associated with an increase in mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase (MEK/Erk) or nuclear factor kappaB (NFkappaB) signaling activity or in NIH3T3-transforming ability. In this study, we examined the effect of colon tumor-associated mutations within the B-Raf glycine-rich loop (G loop) on MEK/Erk and NFkappaB signaling and on the transformation of NIH3T3 fibroblasts or IEC-6 intestinal epithelial cells. Of the six G loop mutations examined, only the B-Raf G468A significantly increased MEK/Erk and NFkappaB signaling and NIH3T3 transformation. Only this mutation induced transformed phenotypes of IEC-6 cells. In contrast, the B-Raf G468E mutation significantly decreased MEK/Erk signaling and NIH3T3 transformation and had no effect on NFkappaB signaling. The B-Raf F467C mutation moderately elevated MEK/Erk signaling and NIH3T3 transformation. The other three B-Raf mutations, R461I, I462S, and G463E, did not increase MEK/Erk or NFkappaB signaling or NIH3T3 transformation. Except for F467C, none of the tumors with B-Raf mutations examined in this study had K-Ras mutations. These results suggest that some of the B-Raf G loop mutations reported in colorectal tumors do not increase kinase or transforming activities but might contribute to carcinogenesis via other mechanisms or be irrelevant to carcinogenesis.
|
| 巻・号 |
64(10)
|
| ページ |
3428-35
|
| 公開日 |
2004-5-15
|
| DOI |
10.1158/0008-5472.CAN-03-3591
|
| PII |
64/10/3428
|
| PMID |
15150094
|
| MeSH |
Amino Acid Sequence
Animals
COS Cells
Cell Adhesion / genetics
Cell Division / genetics
Cell Transformation, Neoplastic / genetics*
Cell Transformation, Neoplastic / metabolism
Chlorocebus aethiops
Colorectal Neoplasms / enzymology
Colorectal Neoplasms / genetics*
Enzyme Activation
Humans
I-kappa B Kinase
MAP Kinase Signaling System / genetics*
Mice
Mitogen-Activated Protein Kinases / genetics
Mitogen-Activated Protein Kinases / metabolism*
Molecular Sequence Data
NF-kappa B / metabolism*
NIH 3T3 Cells
Point Mutation*
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins c-raf / genetics*
Proto-Oncogene Proteins c-raf / metabolism
Sequence Alignment
Signal Transduction
Transcription, Genetic
|
| IF |
9.727
|
| 引用数 |
55
|
|
WOS 分野
|
ONCOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
IEC 6(RCB0993) |
