Protein L-isoaspartyl methyltransferase regulates p53 activity.
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.
Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Jae-Cheol
JC
Lee
Sung-Ung
SU
Kang
Yeji
Y
Jeon
Jong Woo
JW
Park
Jueng-Soo
JS
You
Shin-Won
SW
Ha
Narkhyun
N
Bae
Gert
G
Lubec
So Hee
SH
Kwon
Ju-Seog
JS
Lee
Eun-Jung
EJ
Cho
Jeung-Whan
JW
Han
D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D011485:Protein Binding; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase