eIF4B enhances ATF4 expression and contributes to cellular adaptation to asparagine limitation in BRAF-mutated A375 melanoma
| Autor: | Yukie Iwao, Satomi Tsukahara, Yuka Okamoto, Akihiro Tomida, Hitomi Shirahama |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Proto-Oncogene Proteins B-raf
Biophysics Antineoplastic Agents Biology Biochemistry Transcriptome Eukaryotic initiation factor Tumor Cells Cultured medicine Humans Integrated stress response Eukaryotic Initiation Factors EIF4B Vemurafenib Melanoma Molecular Biology Cell Proliferation Tumor microenvironment ATF4 Cell Biology Activating Transcription Factor 4 Cancer research Asparagine Signal transduction medicine.drug |
| Zdroj: | Biochemical and Biophysical Research Communications. 573:93-99 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2021.08.022 |
| Popis: | ATF4 is a crucial transcription factor in the integrated stress response, a major adaptive signaling pathway activated by tumor microenvironment and therapeutic stresses. BRAF inhibitors, such as vemurafenib, induce ATF4 in BRAF-mutated melanoma cells, but the mechanisms of ATF4 induction are not fully elucidated. Here, we show that ATF4 expression can be upregulated by eukaryotic initiation factor 4B (eIF4B) in BRAF-mutated A375 cells. Indeed, eIF4B knockout (KO) prevented ATF4 induction and activation of the uORF-mediated ATF4 translation mechanism during vemurafenib treatment, which were effectively recovered by the rescue of eIF4B. Transcriptome analysis revealed that eIF4B KO selectively influenced ATF4-target gene expression among the overall gene expression changed by vemurafenib. Interestingly, eIF4B supported cellular proliferation under asparagine-limited conditions, possibly through the eIF4B-ATF4 pathway. Our findings indicate that eIF4B can regulate ATF4 expression, thereby contributing to cellular stress adaptation, which could be targeted as a therapeutic approach against malignancies, including melanoma. |
| Databáze: | OpenAIRE |
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