Gadd45β is transcriptionally activated by p53 via p38α-mediated phosphorylation during myocardial ischemic injury.
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.


CONCLUSIONS
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.
College of Pharmacy, Ajou University, San 5, Wonchon-dong, Yeongtong-gu, Suwon, 443-749, Republic of Korea.
Young-Ae
YA
Kim
Mi-Young
MY
Kim
Hye Yon
HY
Yu
Siddhartha Kumar
SK
Mishra
Jae-Hyeok
JH
Lee
Kyeong Sook
KS
Choi
Jae-Ho
JH
Kim
Yang Kevin
YK
Xiang
Yi-Sook
YS
Jung
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics*; D017209:Apoptosis; D001483:Base Sequence; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D008969:Molecular Sequence Data; D017202:Myocardial Ischemia / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051381:Rats; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D048308:Mitogen-Activated Protein Kinase 14; D016159:Tumor Suppressor Protein p53; C508094:Gadd45b protein, rat; D000097642:GADD45 Proteins