CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis
| Autor: | Michael S. Kilberg, B. Teske, Jeanette N. McClintick, Ronald C. Wek, Michael E. Fusakio, Donghui Zhou, Jixiu Shan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
genetic structures
Leupeptins Eukaryotic Initiation Factor-2 Activating transcription factor Apoptosis CHOP Gene Knockout Techniques Mice 0302 clinical medicine immune system diseases hemic and lymphatic diseases polycyclic compounds Homeostasis Gene Regulatory Networks Phosphorylation Promoter Regions Genetic Cells Cultured Regulation of gene expression Transcription Factor CHOP Feedback Physiological 0303 health sciences eIF2 Articles Activating Transcription Factors Proto-Oncogene Proteins c-bcl-2 030220 oncology & carcinogenesis Thapsigargin Proteasome Inhibitors Transcriptional Activation Cell Survival Biology Cell fate determination Response Elements 03 medical and health sciences Stress Physiological Integrated stress response Animals Molecular Biology 030304 developmental biology ATF4 Cell Biology eye diseases Signaling Gene Expression Regulation Protein Biosynthesis Proteolysis Cancer research Apoptosis Regulatory Proteins Transcriptome Protein Processing Post-Translational |
| Zdroj: | Molecular Biology of the Cell |
| ISSN: | 1939-4586 1059-1524 |
| Popis: | This study addresses the mechanisms by which CHOP directs gene regulatory networks and determines cell fate. Transcriptional expression of ATF5 is activated by both CHOP and ATF4 in the integrated stress response. CHOP and ATF5 control a switch to activate apoptotic genes and decrease cell survival in response to loss of proteostatic control. Environmental stresses that disrupt protein homeostasis induce phosphorylation of eIF2, triggering repression of global protein synthesis coincident with preferential translation of ATF4, a transcriptional activator of the integrated stress response (ISR). Depending on the extent of protein disruption, ATF4 may not be able to restore proteostatic control and instead switches to a terminal outcome that features elevated expression of the transcription factor CHOP (GADD153/DDIT3). The focus of this study is to define the mechanisms by which CHOP directs gene regulatory networks that determine cell fate. We find that in response to proteasome inhibition, CHOP enhances the expression of a collection of genes encoding transcription regulators, including ATF5, which is preferentially translated during eIF2 phosphorylation. Transcriptional expression of ATF5 is directly induced by both CHOP and ATF4. Knockdown of ATF5 increases cell survival in response to proteasome inhibition, supporting the idea that both ATF5 and CHOP have proapoptotic functions. Transcriptome analysis of ATF5-dependent genes reveals targets involved in apoptosis, including NOXA, which is important for inducing cell death during proteasome inhibition. This study suggests that the ISR features a feedforward loop of stress-induced transcriptional regulators, each subject to transcriptional and translational control, which can switch cell fate toward apoptosis. |
| Databáze: | OpenAIRE |
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