Abstract
Transcription regulates axon outgrowth and regeneration. However, to date, no transcription complexes have been shown to control axon outgrowth and regeneration by regulating axon growth genes. Here, we report that the tumor suppressor p53 and its acetyltransferases CBP/p300 form a transcriptional complex that regulates the axonal growth-associated protein 43, a well-characterized pro-axon outgrowth and regeneration protein. Acetylated p53 at K372-3-82 drives axon outgrowth, GAP-43 expression, and binds specific elements on the neuronal GAP-43 promoter in a chromatin environment through CBP/p300 signaling. Importantly, in an axon regeneration model, both CBP and p53 K372-3-82 are induced following axotomy in facial motor neurons, where p53 K372-3-82 occupancy of GAP-43 promoter is enhanced as shown by in vivo chromatin immunoprecipitation. Finally, by comparing wild-type and p53 null mice, we demonstrate that the p53/GAP-43 transcriptional module is specifically switched on during axon regeneration in vivo. These data contribute to the understanding of gene regulation in axon outgrowth and may suggest new molecular targets for axon regeneration.
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Abbreviations
- C/EBP:
-
CCAAT-enhancer-binding proteins
- CBP:
-
CREB-binding protein
- CREB:
-
cAMP-responsive element-binding protein
- JNKs:
-
c-Jun N-terminal kinases
- MAPK:
-
mitogen-activated protein kinases
- NFAT:
-
nuclear factor of activated T-cells
- P/CAF:
-
p300/CBP-associated factor
- STAT3:
-
signal transducer and activator of transcription 3
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Acknowledgements
We thank Jorge Garay for conducting part of the facial nerve transection experiments, Sergio Schinelli for critically reviewing the paper, and Sanam Vakil for her help editing the paper. In addition, we are grateful to Dr. Maria Laura Avantaggiati for providing the p53 acetylation mutant plasmid DNAs, to Dr. Ulrike Neumann for the p53 R273H and R248W mutant plasmid DNAs, and to Dr. Katsuhide Miyake for providing the CBP/p300 RNAi. This work was supported by the Hertie Foundation; the Fortune Grant, University of Tuebingen, the NIH R21 NS052640 and the DFG DI 1497/1-1 grants (all granted to Simone Di Giovanni).
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Tedeschi, A., Nguyen, T., Puttagunta, R. et al. A p53-CBP/p300 transcription module is required for GAP-43 expression, axon outgrowth, and regeneration. Cell Death Differ 16, 543–554 (2009). https://doi.org/10.1038/cdd.2008.175
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DOI: https://doi.org/10.1038/cdd.2008.175
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