Depletion of eukaryotic initiation factor 5B (eIF5B) reprograms the cellular transcriptome and leads to activation of endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK).
dc.contributor.author | Bressler, Kamiko R. | |
dc.contributor.author | Ross, Joseph A. | |
dc.contributor.author | Ilnytskyy, Slava | |
dc.contributor.author | Vanden Dungen, Keiran | |
dc.contributor.author | Taylor, Katrina | |
dc.contributor.author | Patel, Kush | |
dc.contributor.author | Zovoilis, Athanasios | |
dc.contributor.author | Kovalchuk, Igor | |
dc.contributor.author | Thakor, Nehal | |
dc.date.accessioned | 2020-11-05T19:14:33Z | |
dc.date.available | 2020-11-05T19:14:33Z | |
dc.date.issued | 2021 | |
dc.description | Accepted author manuscript. | en_US |
dc.description.abstract | During the integrated stress response (ISR), global translation initiation is attenuated; however, noncanonical mechanisms allow for the continued translation of specific transcripts. Eukaryotic initiation factor 5B (eIF5B) has been shown to play a critical role in canonical translation as well as in noncanonical mechanisms involving internal ribosome entry site (IRES) and upstream open reading frame (uORF) elements. The uORF-mediated translation regulation of activating transcription factor 4 (ATF4) mRNA plays a pivotal role in the cellular ISR. Our recent study confirmed that eIF5B depletion removes uORF2-mediated repression of ATF4 translation, which results in the upregulation of growth arrest and DNA damage-inducible protein 34 (GADD34) transcription. Accordingly, we hypothesized that eIF5B depletion may reprogram the transcriptome profile of the cell. Here, we employed genome-wide transcriptional analysis on eIF5B-depleted cells. Further, we validate the up- and downregulation of several transcripts from our RNA-seq data using RT-qPCR. We identified upregulated pathways including cellular response to endoplasmic reticulum (ER) stress, and mucin-type O-glycan biosynthesis, as well as downregulated pathways of transcriptional misregulation in cancer and T cell receptor signaling. We also confirm that depletion of eIF5B leads to activation of the c-Jun N-terminal kinase (JNK) arm of the mitogen-activated protein kinase (MAPK) pathway. This data suggests that depletion of eIF5B reprograms the cellular transcriptome and influences critical cellular processes such as ER stress and ISR. | en_US |
dc.description.peer-review | Yes | en_US |
dc.identifier.citation | Bressler, K. R., Ross, J. A., Ilnytskyy, S., Vanden Dungen, K., Taylor, K., Patel, K., Zovoilis, A., Kovalchuk, I., & Thakor, N (2021). Depletion of eukaryotic initiation factor 5B (eIF5B) reprograms the cellular transcriptome and leads to activation of endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK). Cell Stress and Chaperones, 26, 253-264. https://doi.org/10.1007/s12192-020-01174-1 | en_US |
dc.identifier.uri | https://hdl.handle.net/10133/5801 | |
dc.language.iso | en_US | en_US |
dc.publisher | Springer | en_US |
dc.publisher.department | Department of Chemistry and Biochemistry | en_US |
dc.publisher.department | Department of Biological Sciences | en_US |
dc.publisher.department | Department of Neuroscience | en_US |
dc.publisher.faculty | Arts and Science | en_US |
dc.publisher.institution | University of Lethbridge | en_US |
dc.publisher.institution | University of Calgary | en_US |
dc.publisher.url | https://doi.org/10.1007/s12192-020-01174-1 | en_US |
dc.subject | Eukaryotic initiation factor 5B (eIF5B) | en_US |
dc.subject | ER stress | en_US |
dc.subject | Transcriptome | en_US |
dc.subject | ISR | en_US |
dc.subject | ATF4 | en_US |
dc.subject | JNK | en_US |
dc.title | Depletion of eukaryotic initiation factor 5B (eIF5B) reprograms the cellular transcriptome and leads to activation of endoplasmic reticulum (ER) stress and c-Jun N-terminal Kinase (JNK). | en_US |
dc.type | Article | en_US |
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