Reference - Detail
| RRC ID | 52460 |
|---|---|
| Author | Kanno E, Kawasaki O, Takahashi K, Takano K, Endo T. |
| Title | DA-Raf, a dominant-negative antagonist of the Ras-ERK pathway, is a putative tumor suppressor. |
| Journal | Exp Cell Res |
| Abstract |
Activating mutations of RAS genes, particularly KRAS, are detected with high frequency in human tumors. Mutated Ras proteins constitutively activate the ERK pathway (Raf-MEK-ERK phosphorylation cascade), leading to cellular transformation and tumorigenesis. DA-Raf1 (DA-Raf) is a splicing variant of A-Raf and contains the Ras-binding domain (RBD) but lacks the kinase domain. Accordingly, DA-Raf antagonizes the Ras-ERK pathway in a dominant-negative fashion and suppresses constitutively activated K-Ras-induced cellular transformation. Thus, we have addressed whether DA-Raf serves as a tumor suppressor of Ras-induced tumorigenesis. DA-Raf(R52Q), which is generated from a single nucleotide polymorphism (SNP) in the RBD, and DA-Raf(R52W), a mutant detected in a lung cancer, neither bound to active K-Ras nor interfered with the activation of the ERK pathway. They were incapable of suppressing activated K-Ras-induced cellular transformation and tumorigenesis in mice, in which K-Ras-transformed cells were transplanted. Furthermore, although DA-Raf was highly expressed in lung alveolar epithelial type 2 (AE2) cells, its expression was silenced in AE2-derived lung adenocarcinoma cell lines with oncogenic KRAS mutations. These results suggest that DA-Raf represents a tumor suppressor protein against Ras-induced tumorigenesis. |
| Volume | 362(1) |
| Pages | 111-120 |
| Published | 2018-1-1 |
| DOI | 10.1016/j.yexcr.2017.11.008 |
| PII | S0014-4827(17)30615-8 |
| PMID | 29129563 |
| MeSH | A549 Cells Adenocarcinoma / genetics Adenocarcinoma of Lung Animals COS Cells Carcinogenesis / genetics Cell Line Cell Line, Tumor Chlorocebus aethiops Dogs Genes, ras / genetics* HCT116 Cells HL-60 Cells HeLa Cells Humans Lung Neoplasms / genetics MAP Kinase Signaling System / genetics* Madin Darby Canine Kidney Cells Mice NIH 3T3 Cells Proto-Oncogene Proteins A-raf / genetics* Tumor Suppressor Proteins / genetics* ras Proteins / genetics* |
| IF | 3.383 |
| Times Cited | 2 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | News |
| Total number of mentions | 2 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | LU65(RCB1967) HCT116(RCB2979) |