Histone Arg modifications and p53 regulate the expression of OKL38, a mediator of apoptosis.
Protein Arg methyltransferases function as coactivators of the tumor suppressor p53 to regulate gene expression. Peptidylarginine deiminase 4 (PAD4/PADI4) counteracts the functions of protein Arg methyltransferases in gene regulation by deimination and demethylimination. Here we show that the expression of a tumor suppressor gene, OKL38, is activated by the inhibition of PAD4 or the activation of p53 following DNA damage. Chromatin immunoprecipitation assays showed a dynamic change of p53 and PAD4 occupancy and histone Arg modifications at the OKL38 promoter during DNA damage, suggesting a direct role of PAD4 and p53 in the expression of OKL38. Furthermore, we found that OKL38 induces apoptosis through localization to mitochondria and induction of cytochrome c release. Together, our studies identify OKL38 as a novel p53 target gene that is regulated by PAD4 and plays a role in apoptosis.
Yao
Hongjie
H
Center for Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
Li
Pingxin
P
Venters
Bryan J
BJ
Zheng
Suting
S
Thompson
Paul R
PR
Pugh
B Franklin
BF
Wang
Yanming
Y
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D006657:Histones; C432368:OSGIN1 protein, human; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D045304:Cytochromes c; D001120:Arginine; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases