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Mutant TP 53 Posttranslational Modifications: Challenges and Opportunities
Author(s) -
Nguyen ThuyAi,
Menendez Daniel,
Resnick Michael A.,
Anderson Carl W.
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22506
Subject(s) - biology , mutant , signal transduction , suppressor , missense mutation , gene , transcription factor , tumor progression , microbiology and biotechnology , mutation , mutant protein , genetics , cancer research
The wild‐type ( WT ) human p53 ( TP 53) tumor suppressor can be posttranslationally modified at over 60 of its 393 residues. These modifications contribute to changes in TP 53 stability and in its activity as a transcription factor in response to a wide variety of intrinsic and extrinsic stresses in part through regulation of protein–protein and protein– DNA interactions. The TP 53 gene frequently is mutated in cancers, and in contrast to most other tumor suppressors, the mutations are mostly missense often resulting in the accumulation of mutant ( MUT ) protein, which may have novel or altered functions. Most MUT TP 53s can be posttranslationally modified at the same residues as in WT TP 53. Strikingly, however, codons for modified residues are rarely mutated in human tumors, suggesting that TP 53 modifications are not essential for tumor suppression activity. Nevertheless, these modifications might alter MUT TP 53 activity and contribute to a gain‐of‐function leading to increased metastasis and tumor progression. Furthermore, many of the signal transduction pathways that result in TP53 modifications are altered or disrupted in cancers. Understanding the signaling pathways that result in TP 53 modification and the functions of these modifications in both WT TP 53 and its many MUT forms may contribute to more effective cancer therapies.