Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1303-1313 |
| Number of pages | 11 |
| Journal | Journal of Molecular Medicine |
| Volume | 91 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2013 |
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Keywords
- Anoxia
- Growth arrest and DNA damage-inducible 45β
- H9c2 cells
- p38α
- p53
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
- Genetics(clinical)
Cite this
Gadd45β is transcriptionally activated by p53 via p38α-mediated phosphorylation during myocardial ischemic injury. / Kim, Young Ae; Kim, Mi Young; Yu, Hye Yon; Mishra, Siddhartha Kumar; Lee, Jae Hyeok; Choi, Kyeong Sook; Kim, Jae Ho; Xiang, Yang Kevin; Jung, Yi Sook.
In: Journal of Molecular Medicine, Vol. 91, No. 11, 11.2013, p. 1303-1313.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Gadd45β is transcriptionally activated by p53 via p38α-mediated phosphorylation during myocardial ischemic injury
AU - Kim, Young Ae
AU - Kim, Mi Young
AU - Yu, Hye Yon
AU - Mishra, Siddhartha Kumar
AU - Lee, Jae Hyeok
AU - Choi, Kyeong Sook
AU - Kim, Jae Ho
AU - Xiang, Yang Kevin
AU - Jung, Yi Sook
PY - 2013/11
Y1 - 2013/11
N2 - 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.
AB - 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.
KW - Anoxia
KW - Growth arrest and DNA damage-inducible 45β
KW - H9c2 cells
KW - p38α
KW - p53
UR - http://www.scopus.com/inward/record.url?scp=84888639427&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84888639427&partnerID=8YFLogxK
U2 - 10.1007/s00109-013-1070-9
DO - 10.1007/s00109-013-1070-9
M3 - Article
C2 - 23948959
AN - SCOPUS:84888639427
VL - 91
SP - 1303
EP - 1313
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
SN - 0946-2716
IS - 11
ER -