Regulation of TP53 Activity through Phosphorylation

Phosphorylation of TP53 at serine residue S46 promotes transcription of TP53-regulated apoptotic genes rather than cell cycle arrest genes. Several kinases can phosphorylate S46 of TP53, including ATM-activated DYRK2, which, like TP53, is targeted for degradation by MDM2. TP53 is also phosphorylated at S46 by HIPK2 in the presence of the TP53 transcriptional target TP53INP1. CDK5, in addition to phosphorylating TP53 at S15, also phosphorylates it at S33 and S46, which promotes neuronal cell death.

MAPKAPK5 (PRAK) phosphorylates TP53 at serine residue S37, promoting cell cycle arrest and cellular senescence in response to oncogenic RAS signaling.

NUAK1 phosphorylates TP53 at S15 and S392, and phosphorylation at S392 may contribute to TP53-mediated transcriptional activation of cell cycle arrest genes. S392 of TP53 is also phosphorylated by the complex of casein kinase II (CK2) bound to the FACT complex, enhancing transcriptional activity of TP53 in response to UV irradiation.

The activity of TP53 is inhibited by phosphorylation at serine residue S315, which enhances MDM2 binding and degradation of TP53. S315 of TP53 is phosphorylated by Aurora kinase A (AURKA) and CDK2. Interaction with MDM2 and the consequent TP53 degradation is also increased by phosphorylation of TP53 threonine residue T55 by the transcription initiation factor complex TFIID.

Aurora kinase B (AURKB) has been shown to phosphorylate TP53 at serine residue S269 and threonine residue T284, which is possibly facilitated by the binding of the NIR co-repressor. AURKB-mediated phosphorylation was reported to inhibit TP53 transcriptional activity through an unknown mechanism. A putative direct interaction between TP53 and AURKB has also been described and linked to TP53 phosphorylation and S183, T211 and S215 and TP53 degradation.