Regulation of TP53 Activity

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R-HSA-5633007
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Pathway
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Homo sapiens
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Protein stability and transcriptional activity of TP53 (p53) tumor suppressor are regulated by post-translational modifications that include ubiquitination, phosphorylation, acetylation, methylation, sumoylation and prolyl-isomerization (Kruse and Gu 2009, Meek and Anderson 2009, Santiago et al. 2013, Mantovani et al. 2015). In addition to post-translational modifications, the activity of TP53 is also regulated by binding of transcription co-factors.

In unstressed cells, TP53 protein levels are low due to MDM2-mediated ubiquitination of TP53, which triggers proteasome-mediated degradation. In response to stress, TP53 undergoes stabilizing phosphorylation, mainly at serine residues S15 and S20. Several different kinases can phosphorylate TP53 at these sites, but the main S15 kinases are considered to be ATM and ATR, while the main S20 kinases are considered to be CHEK2 and CHEK1. Additional phosphorylation of TP53 at serine residue S46 promotes transcription of pro-apoptotic, rather than cell cycle arrest genes.

Acetylation mainly has a positive impact on transcriptional activity of TP53, while methylation can both positively and negatively regulate TP53.

Some posttranslational modifications regulate interaction of TP53 with transcriptional co-factors, some of which are themselves transcriptional targets of TP53.

For review of the complex network of TP53 regulation, please refer to Kruse and Gu 2009, and Meek and Anderson 2009.

Literature References
PubMed ID Title Journal Year
19450511 Modes of p53 regulation

Kruse, JP, Gu, W

Cell 2009
20457558 Posttranslational modification of p53: cooperative integrators of function

Meek, DW, Anderson, CW

Cold Spring Harb Perspect Biol 2009
23825024 p53 SUMOylation promotes its nuclear export by facilitating its release from the nuclear export receptor CRM1

Santiago, A, Li, D, Zhao, LY, Godsey, A, Liao, D

Mol. Biol. Cell 2013
25641576 Interaction of p53 with prolyl isomerases: Healthy and unhealthy relationships

Mantovani, F, Zannini, A, Rustighi, A, Del Sal, G

Biochim. Biophys. Acta 2015
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