Gadd45β is transcriptionally activated by p53 via p38α-mediated phosphorylation during myocardial ischemic injury.
Kim, YA; Kim, MY; Yu, HY; Mishra, SK; Lee, JH; Choi, KS; Kim, JH; Xiang, YK; Jung, YS
Journal of molecular medicine, 91(11):1303-1313, 2013
Journal of molecular medicine
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.
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