JNK-dependent phosphorylation and nuclear translocation of EGR-1 promotes cardiomyocyte apoptosis

Myocardial apoptosis induced by myocardial ischemia and hyperlipemia are the main causes of high mortality of cardiovascular diseases. It is not clear whether there is a common mechanism responsible for these two kinds of cardiomyocyte apoptosis. Previous studies demonstrated that early growth respo...

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Published in:Apoptosis (London) 2022-04, Vol.27 (3-4), p.246-260
Main Authors: Zhou, Jinrun, Yao, Yujuan, Zhang, Jiaojiao, Wang, Zhaohui, Zheng, Tianshu, Lu, Yao, Kong, Weihua, Zhao, Jing
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis Regulatory Proteins - metabolism
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cardiomyocytes
Cardiovascular Diseases
Cell Biology
Early Growth Response Protein 1 - genetics
Early Growth Response Protein 1 - metabolism
Early Growth Response Protein 1 - pharmacology
EGR-1 protein
Humans
Ischemia
mRNA
Myocardial ischemia
Myocytes, Cardiac - metabolism
Nuclear transport
Nucleation
Oncology
Phosphorylation
Plasmids
Proteins
Translocation
Virology
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Summary:Myocardial apoptosis induced by myocardial ischemia and hyperlipemia are the main causes of high mortality of cardiovascular diseases. It is not clear whether there is a common mechanism responsible for these two kinds of cardiomyocyte apoptosis. Previous studies demonstrated that early growth response protein 1 (EGR-1) has a pro-apoptotic effect on cardiomyocytes under various stress conditions. Here, we found that EGR-1 is also involved in cardiomyocyte apoptosis induced by both ischemia and high-fat, but how EGR-1 enters the nucleus and whether nuclear EGR-1 (nEGR-1) has a universal effect on cardiomyocyte apoptosis are still unknown. By analyzing the phosphorylation sites and nucleation information of EGR-1, we constructed different mutant plasmids to confirm that the nucleus location of EGR-1 requires Ser501 phosphorylation and regulated by JNK. Furthermore, the pro-apoptotic effect of nEGR-1 was further explored through genetic methods. The results showed that EGR-1 positively regulates the mRNA levels of apoptosis-related proteins (ATF2, CTCF, HAND2, ELK1), which may be the downstream targets of EGR-1 to promote the cardiomyocyte apoptosis. Our research announced the universal pro-apoptotic function of nEGR-1 and explored the mechanism of its nucleus location in cardiomyocytes, providing a new target for the “homotherapy for heteropathy” to cardiovascular diseases.
ISSN:1360-8185
1573-675X
DOI:10.1007/s10495-022-01714-3