Critical loss of CBP/p300 histone acetylase activity by caspase‐6 during neurodegeneration
Open accessAbstract
By altering chromatin structure, histone acetyltransferases (HATs) act as transcriptional regulators. We observed in a model of primary neurons that histone acetylation levels decreased at the onset of apoptosis. The CREB-binding protein (CBP) is a HAT of particular interest because it also acts as a co-activator controlling, among others, CREB-dependent transcriptional activity. It has been demonstrated that CREB exerts neuroprotective functions, but the fate of CBP during neuronal apoptosis remained unclear till now. This work provided evidence that CBP is specifically targeted by caspases and calpains at the onset of neuronal apoptosis, and CBP was futher identified as a new caspase-6 substrate. This ultimately impinged on the CBP/p300 HAT activity that decreased with time during apoptosis entry, whereas total cellular HAT activity remained unchanged. Interestingly, CBP loss and histone deacetylation were observed in two different pathological contexts: amyloid precursor protein-dependent signaling and amyotrophic lateral sclerosis model mice, indicating that these modifications are likely to contribute to neurodegenerative diseases. In terms of function, we demonstrated that fine-tuning of CBP HAT activity is necessary to ensure neuroprotection.
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No difference was found in the levels of P300, cREL or NFATc in rTg4510 mice.
“No difference was found in the levels of P300, cREL or NFATc (data not shown), transcription factors that have been implicated in different neurodegeneration models (73 -76).”
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- Authors
- Rouaux, C., Jokic, N., Mbebi, C., Boutillier, S., Loeffler, J., & Boutillier, A.
- Corresponding author
- Boutillier, Anne‐Laurence
- Venue
- The EMBO Journal
- Published
- 2003-12-15
- Volume
- 22
- Issue
- 24
- Pages
- 6537-6549
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC291810
- OpenAlex
- W1998707569
- Cited by
- 302
- References
- 45
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 12 · 2023: 7 · 2022: 11 · 2021: 7 · 2020: 15 · 2019: 10 · 2018: 16 · 2017: 15 · 2016: 9 · 2015: 16 · 2014: 14 · 2013: 24 · 2012: 18
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- ALS Association
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- CREB-binding protein, P300, histone acetyltransferase activity, caspase-6, neuronal apoptosis, neurodegeneration, histone deacetylation, calpain, amyotrophic lateral sclerosis, CREB-dependent transcription, neuroprotection, chromatin structure
- MeSH terms
- p300-CBP-Associated Factor, Acetyltransferases, Animals, Cell Survival, Cells, Cultured, Cerebellum, Histones, Hydrolysis, Kinetics, Mice, Inbred Strains, Nerve Degeneration, Neurons, Recombinant Proteins, Transcription Factors, Apoptosis, Cyclic AMP Response Element-Binding Protein, Cell Cycle Proteins, Reverse Transcriptase Polymerase Chain Reaction, Caspases, p300-CBP Transcription Factors, Mice, Histone Acetyltransferases, Caspase 6
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