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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.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Ikenoue, Tsuneo Hikiba, Yohko Kanai, Fumihiko Aragaki, Jun Tanaka, Yasuo Imamura, Jun Imamura, Takaaki Ohta, Miki Ijichi, Hideaki Tateishi, Keisuke Kawakami, Takayuki Matsumura, Masayuki Kawabe, Takao Omata, Masao |
| Copyright Year | 2004 |
| 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. |
| File Format | PDF HTM / HTML |
| DOI | 10.1158/0008-5472.CAN-03-3591 |
| PubMed reference number | 15150094 |
| Journal | Medline |
| Volume Number | 64 |
| Issue Number | 10 |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/64/10/3428.full.pdf |
| Alternate Webpage(s) | https://doi.org/10.1158/0008-5472.CAN-03-3591 |
| Journal | Cancer research |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
