Publications by authors named "Danni Meng"

2 Publications

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Exercise downregulates HIPK2 and HIPK2 inhibition protects against myocardial infarction.

EBioMedicine 2021 Dec 24;74:103713. Epub 2021 Nov 24.

Shanghai Engineering Research Center of Organ Repair, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai, 200444, China. Electronic address:

Background: Exercise can protect myocardial infarction (MI) and downregulate cardiac Homeodomain-Interacting Protein Kinase 2 (HIPK2). However, the role of HIPK2 in MI is unclear.

Methods: HIPK2 mice and miR-222 rats, HIPK2 inhibitor (PKI1H) and adeno-associated virus serotype 9 (AAV9) carrying miR-222 were applied in the study. Animals were subjected to running, swimming, acute MI or post-MI remodeling. HIPK2 inhibition and P53 activator were used in neonatal rat cardiomyocytes (NRCMs) and human embryonic stem cell-derived cardiomyocytes (hESC-CMs) subjected to oxygen glucose deprivation/reperfusion (OGD/R). Serum miR-222 levels were analyzed in healthy people and MI patients that were survival or readmitted to the hospital and/or died.

Findings: Cardiac HIPK2 protein levels were reduced by exercise while increased in MI. In vitro, HIPK2 suppression by lentiviral vectors or inhibitor prevented apoptosis induced by OGD/R in NRCMs and hESC-CMs. HIPK2 inhibitor-treated mice and HIPK2 mice reduced infarct size after acute MI, and preserved cardiac function in MI remodeling. Mechanistically, protective effect against apoptosis by HIPK2 suppression was reversed by P53 activators. Furthermore, increasing levels of miR-222, targeting HIPK2, protected post-MI cardiac dysfunction, whereas cardiac dysfunction post-MI was aggravated in miR-222 rats. Moreover, serum miR-222 levels were significantly reduced in MI patients, as well as in MI patients that were readmitted to the hospital and/or died compared to those not.

Interpretation: Exercise-induced HIPK2 suppression attenuates cardiomyocytes apoptosis and protects MI by decreasing P-P53. Inhibition of HIPK2 represents a potential novel therapeutic intervention for MI.

Funding: This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to JJ Xiao), National Natural Science Foundation of China (82020108002, 81722008, and 81911540486 to JJ Xiao, 81400647 to MJ Xu, 81800265 to YJ Liang), Innovation Program of Shanghai Municipal Education Commission (2017-01-07-00-09-E00042 to JJ Xiao), the grant from Science and Technology Commission of Shanghai Municipality (18410722200 and 17010500100 to JJ Xiao), the "Dawn" Program of Shanghai Education Commission (19SG34 to JJ Xiao), Shanghai Sailing Program (21YF1413200 to QL Zhou). JS is supported by Horizon2020 ERC-2016-COG EVICARE (725229).
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December 2021

Ring finger 20/ring finger 40/WW domain-containing adaptor with coiled-coil complex interacts with p53 to regulate gene transcription in DNA damage response.

Oncol Lett 2021 Jun 1;21(6):436. Epub 2021 Apr 1.

College of Life Sciences, Shanghai Normal University, Shanghai 200234, P.R. China.

p53 is one of the most important tumor suppressor genes, and its primary function is to act as a transcriptional activator to control cell cycle arrest, DNA repair and cellular metabolism by recognizing and binding to specific DNA sequences. Defects in the ring finger (RNF)20/RNF40/WW domain-containing adaptor with coiled-coil (WAC) complex, one of the histone H2B ubiquitination E3 ligases, have been reported to be a key factor in oncogenesis, cancer cell migration and invasion. Histone H2B mono-ubiquitination has been demonstrated to be essential for maintaining the functionality of the p53 tumor suppressor protein. The aim of the present study was to identify any sites in the p53 DNA-binding domain (DBD) specific to the RNF20/RNF40/WAC complex that may be involved in the gene regulation in DNA damage response. The results demonstrated that p53 and the RNF20/RNF40/WAC complex interacted with each other, and the coiled-coil regions in RNF20, RNF40 and WAC were identified to directly interact with p53. The R282 site in the p53 DBD, one of the frequent missense mutations associated with p53 mutation-dependent cancer, was demonstrated to be the key binding site for the RNF20/RNF40/WAC complex. Furthermore, knockout of RNF20/RNF40 suppressed the expression levels of p53 and its target genes in HCT116 cells compared with those in wild-type HCT116 cells. Consistent with these results, the R282W mutation in p53 inhibited the expression levels of p53 and its downstream genes by inactivating the interaction between p53 and RNF20/RNF40 compared with those in wild-type HCT116 cells. In conclusion, the results of the present study revealed the molecular mechanism of the interaction between the RNF20/RNF40/WAC complex and p53, and demonstrated that these proteins regulated gene transcription in the DNA damage response.
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June 2021