Gadd45β is transcriptionally activated by p53 via p38α-mediated phosphorylation during myocardial ischemic injury
Abstract
Unlabelled Growth arrest and DNA damage-inducible 45β (Gadd45β) have been shown to play a role in inducing cardiomyocyte apoptosis under ischemia/anoxia. The well-known transcription factor p53 is known to cause apoptosis in cardiomyocytes under ischemia. Based on the common role of Gadd45β and p53 in ischemia-induced apoptosis, we investigated whether p53 is involved in the mechanisms responsible for Gadd45β expression in both in vitro and in vivo models of ischemic heart injury. A chromatin immunoprecipitation assay revealed direct binding of p53 to the Gadd45β promoter region during anoxia, and this binding was confirmed by surface plasmon resonance imaging. In rat heart-derived H9c2 cells, silencing of p53 abrogated the increase of Gadd45β promoter-luciferase reporter (Gadd45β-Luc) activity and the expression of Gadd45β under anoxia and overexpression of p53 enhanced Gadd45β-Luc activity and Gadd45β expression. Gadd45β mRNA and protein expression were significantly inhibited by p53 siRNA in a rat ischemic heart model. In addition, p38α-mediated phophorylation of p53 at both Ser15 and Ser20 was shown to be essential for the expression of Gadd45β mRNA and protein during anoxia. These results reveal the p38α-p53-Gadd45β axis as a novel signaling module in the anoxia-induced apoptotic death pathway. In conclusion, this study provides molecular evidence that Gadd45β is a novel downstream target gene of p53 under ischemia/anoxia and suggests the therapeutic potential of targeting Gadd45β as a treatment of ischemic heart injury.Key message Gadd45β is transcriptionally induced by p53 via direct binding under ischemia/anoxia. The induction of Gadd45β expression requires the p53 phosphorylation at Ser15/Ser20. p38α mediates the p53 phosphorylation at Ser15/Ser20 and the Gadd45β expression. Ischemia/anoxia-p38α-p53-Gadd45β axis serves as a novel apoptotic signaling module.
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Quantitative proteomic analysis of protein expression changes conferred by asukamycin treatment in 231MFP cells showed many known p53 transcriptional targets upregulated, including GADD45A, GADD45B, ANKRD1, HMOX1, ATF3, PMAIP1, DDIT4, DNAJB9, and PLK2.
“quantitative proteomic analysis of protein expression changes conferred by asukamycin treatment in 231MFP cells showed many known p53 transcriptional targets upregulated in expression, including GADD45A, GADD45B, ANKRD1, HMOX1, ATF3, PMAIP1, DDIT4, DNAJB9, and PLK2 (Extended Data Figure 9) 31–37.”
From Manumycin polyketides act as molecular glues between UBR7 and P53 (2020) · cites this paper as [31]
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Manumycin polyketides act as molecular glues between UBR7 and P53
Isobe, Y., Okumura, M., McGregor, L. M., Brittain, S. M., Jones, M. D., Liang, X., White, R., Forrester, W., McKenna, J. M., Tallarico, J. A., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0557-2 · Cited by 124 · see citing works
- Authors
- Kim, Y.-A., Kim, M.-Y., Yu, H. Y., Mishra, S. K., Lee, J.-H., Choi, K. S., Kim, J.-H., Xiang, Y. K., & Jung, Y.-S.
- Affiliations
- Ajou University (KR)
- University of California, Davis (US)
- Corresponding author
- Jung, Yi-Sook
- Venue
- Journal of Molecular Medicine
- Published
- 2013-08-16
- Volume
- 91
- Issue
- 11
- Pages
- 1303-1313
- ISSN
- 0946-2716 (ISSN-L)
- 1432-1440
- OpenAlex
- W2032039392
- Cited by
- 26
- References
- 34
- Citations by year
- 2025: 1 · 2024: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 1 · 2017: 5 · 2016: 4 · 2015: 3 · 2014: 1
- FWCI
- 1.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- GADD45B, p53, p38 MAPK, myocardial ischemia, anoxia, cardiomyocyte apoptosis, p53 phosphorylation, transcriptional activation, myocardial ischemic injury, p53 target genes
- MeSH terms
- GADD45 Proteins, Animals, Antigens, Differentiation, Base Sequence, Molecular Sequence Data, Phosphorylation, Promoter Regions, Genetic, Transcriptional Activation, Tumor Suppressor Protein p53, Myocardial Ischemia, Apoptosis, Myocytes, Cardiac, Mitogen-Activated Protein Kinase 14, Rats
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