Publication: Protein methylation, a new mechanism of p53 tumor suppressor regulation
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Date
2008
Authors
Scoumanne, A. ; Chen, X.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
The tumor suppressor p53 is the most
frequently inactivated gene in human cancers. The p53
protein functions as a sequence-specific transcription
factor to regulate key cellular processes, including cellcycle
arrest, DNA repair, apoptosis, and senescence in
response to stress signals. P53 is maintained at a low
level in the cell, but becomes rapidly stabilized and
activated in response to DNA damage, hypoxia,
hyperproliferation, and other types of cellular stresses.
The stability and transcriptional activity of p53 are
tightly regulated through multiple post-translational
modifications, such as phosphorylation, acetylation, and
ubiquitination. Within the past few years, several studies
have established that protein methylation is a novel
mechanism by which p53 is regulated. Indeed, histone
lysine methyltransferases KMT5 (Set9), KMT3C
(Smyd2), and KMT5A (Set8) methylate p53 at specific
C-terminal lysines. Lysine methylation enhances or
suppresses p53 transcriptional activity depending on the
methylation site. Furthermore, the lysine-specific
demethylase KDM1 (LSD1) mediates p53 demethylation, which prevents p53 interaction with its
co-activator 53BP1 to induce apoptosis. Finally, protein
arginine methyltransferases CARM1 and PRMT1 are coactivators
of p53 involved in the methylation of histones
H3 and H4 to facilitate p53-mediated transcription. In
response to cellular stresses, the interplay between p53
methylation, demethylation, and other post-translational
modifications fine-tunes the activity of p53 to ultimately
prevent tumor formation.
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