Journal Article

CHOP Potentially Co-Operates with FOXO3a in Neuronal Cells to Regulate PUMA and BIM Expression in Response to ER Stress

Ballestas, Mary E., Ghosh, Arindam P., Roth, Kevin A., Klocke, Barbara J.

2012

Overview

Endoplasmic reticulum (ER) stress-induced apoptosis has been implicated in various neurodegenerative diseases including Parkinson Disease, Alzheimer Disease and Huntington Disease. PUMA (p53 upregulated modulator of apoptosis) and BIM (BCL2 interacting mediator of cell death), pro-apoptotic BH3 domain-only, BCL2 family members, have previously been shown to regulate ER stress-induced cell death, but the upstream signaling pathways that regulate this response in neuronal cells are incompletely defined. Consistent with previous studies, we show that both PUMA and BIM are induced in response to ER stress in neuronal cells and that transcriptional induction of PUMA regulates ER stress-induced cell death, independent of p53. CHOP (C/EBP homologous protein also known as GADD153; gene name Ddit3), a critical initiator of ER stress-induced apoptosis, was found to regulate both PUMA and BIM expression in response to ER stress. We further show that CHOP knockdown prevents perturbations in the AKT (protein kinase B)/FOXO3a (forkhead box, class O, 3a) pathway in response to ER stress. CHOP co-immunoprecipitated with FOXO3a in tunicamycin treated cells, suggesting that CHOP may also regulate other pro-apoptotic signaling cascades culminating in PUMA and BIM activation and cell death. In summary, CHOP regulates the expression of multiple pro-apoptotic BH3-only molecules through multiple mechanisms, making CHOP an important therapeutic target relevant to a number of neurodegenerative conditions.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: AKT protein / Alzheimer's disease / Animals / Apoptosis / Apoptosis - drug effects / Apoptosis - physiology / Apoptosis Regulatory Proteins - genetics / Apoptosis Regulatory Proteins - metabolism / Bcl-2-Like Protein 11 / BIM protein / Biology / Cascades / CCAAT/enhancer-binding protein / Cell activation / Cell death / Cell growth / Cell Survival - drug effects / Cell Survival - physiology / CHOP protein / Deoxyribonucleic acid / DNA / Endoplasmic reticulum / Endoplasmic Reticulum Stress - physiology / Forkhead Box Protein O3 / Forkhead protein / Forkhead Transcription Factors - genetics / Forkhead Transcription Factors - metabolism / FOXO3 protein / Gene expression / Homology / Huntington's disease / Kinases / Medicine / Membrane Proteins - genetics / Membrane Proteins - metabolism / Mice / Mitochondria / Mortality / Movement disorders / Nervous system diseases / Neurodegenerative diseases / Neurological diseases / Neurons / Neurons - cytology / Neurons - drug effects / Neurons - metabolism / p53 Protein / Parkinson disease / Parkinson's disease / Pathology / Phosphorylation / Protein kinases / Proteins / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Proto-Oncogene Proteins c-akt - metabolism / Rodents / Signal transduction / Signal Transduction - drug effects / Signal Transduction - physiology / Signaling / Stress / Stresses / Telencephalon - cytology / Telencephalon - drug effects / Telencephalon - metabolism / Transcription / Transcription Factor CHOP - genetics / Transcription Factor CHOP - metabolism / Transcription factors / Tumor proteins / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - metabolism / Tunicamycin / Tunicamycin - pharmacology