Protein L-isoaspartyl methyltransferase regulates p53 activity

Jae-Cheol Lee, Sung-Ung Kang, Yeji Jeon, Jong Woo Park, Jueng-Soo You, Shin-Won Ha, Narkhyun Bae, Gert Lubec, So Hee Kwon, Ju-Seog Lee, Eun-Jung Cho and Jeung-Whan Han ()
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Jae-Cheol Lee: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University
Sung-Ung Kang: Medical University of Vienna
Yeji Jeon: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University
Jong Woo Park: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University
Jueng-Soo You: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University
Shin-Won Ha: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University
Narkhyun Bae: Medical University of Vienna
Gert Lubec: Medical University of Vienna
So Hee Kwon: College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University
Ju-Seog Lee: M.D. Anderson Cancer Center, University of Texas
Eun-Jung Cho: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University
Jeung-Whan Han: Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University

Nature Communications, 2012, vol. 3, issue 1, 1-10

Abstract: Abstract Protein methylation plays important roles in most, if not all, cellular processes. Lysine and arginine methyltransferases are known to regulate the function of histones and non-histone proteins through the methylation of specific sites. However, the role of the carboxyl-methyltransferase protein L-isoaspartyl methyltransferase (PIMT) in the regulation of protein functions is relatively less understood. Here we show that PIMT negatively regulates the tumour suppressor protein p53 by reducing p53 protein levels, thereby suppressing the p53-mediated transcription of target genes. In addition, PIMT depletion upregulates the proapoptotic and checkpoint activation functions of p53. Moreover, PIMT destabilizes p53 by enhancing the p53–HDM2 interaction. These PIMT effects on p53 stability and activity are attributed to the PIMT-mediated methylation of p53 at isoaspartate residues 29 and 30. Our study provides new insight into the molecular mechanisms by which PIMT suppresses the p53 activity through carboxyl methylation, and suggests a therapeutic target for cancers.

Date: 2012
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DOI: 10.1038/ncomms1933

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