Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation

Abstract

Components of the ras signaling pathway contribute to activation of cellular p53. In MCF-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at Ser33 and Ser46, a newly identified site. Mutation of these sites decreased p53-mediated and UV-induced apoptosis, and the reduction correlated with total abrogation of UV-induced phosphorylation on Ser37 and a significant decrease in Ser15 phosphorylation in mutant p53 containing alanine at Ser33 and Ser46. Inhibition of p38 activation after UV irradiation decreased phosphorylation of Ser33, Ser37 and Ser15, and also markedly reduced UV-induced apoptosis in a p53-dependent manner. These results suggest that p38 kinase plays a prominent role in an integrated regulation of N-terminal phosphorylation that regulates p53-mediated apoptosis after UV radiation.

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

“…We also demonstrated that aberrant ribosome biogenesis elicits both p38 activation and p53 phosphorylation at serines 15 and 33 (Figure 2c). Although several lines of evidence showed p38-mediated p53 activation and stabilization through direct phosphorylation of critical residues (Bulavin et al, 1999;Bode and Dong, 2004), it is possible that p53 was activated by an alternative pathway because p53 phosphorylation of serine 15, comparing with serine 33, was not remarkably abolished after p38 inhibition through either inhibitors or siRNA. Therefore, we cannot exclude the possibility that serine 15 phosphorylation is affected by unknown kinases responsible for ribosomal stress.…”

“…We identified two serine residues, serine 15 and serine 33, that are remarkably phosphorylated by rpS3 knockdown (Figure 2b). These data lead to the speculation that the p38-dependent phosphorylation is involved in the p53 induction, since it has been demonstrated previously that the phosphorylation at these sites is regulated mainly by p38 kinase (Bulavin et al, 1999;Lavin and Gueven, 2006), and has an effect on the stability and activity of p53 (Bulavin et al, 1999;Kishi et al, 2001).…”

Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK–mediated activation of the p16Ink4a-p19Arf pathway

“…(a) Activation of p53-mediated transcription was analyzed in wild-type (WT) and Ppm1d-null MEFs expressing E1A and Hras1 using CAT reporters linked to a basal promoter containing the wild-type (PG13-CAT) or mutated (MG15-CAT) p53-response elements. CAT assays were carried out as described 11 ; an arrow marks the position of acetylated chloramphenicol. The levels of p53 in nuclear extracts 35 were determined using western immunoblotting.…”

“…In turn, the p38 MAPK pathway has been implicated as a negative regulator of cell cycle progression by several mechanisms, which implies that Wip1 is also an important regulator of cell cycle progression. p38 MAP kinase inhibits expression of D-type cyclins at transcriptional and post-translational levels 7,8 , phosphorylates and induces degradation of the Cdc25A phosphatase 9 , inhibits the Cdc25B phosphatase through phosphorylation of 14-3-3 sites 10 and phosphorylates the p53 tumor suppressor on two activating sites (Ser33 and Ser46) in the N-terminal region, which contribute to p53-mediated apoptosis 2,11 . Together, these p38 MAPK targets cooperate to activate cell cycle checkpoints, which implies that defects in p38 MAPK regulation or function may perturb cell cycle progression leading to increased tumorigenesis.…”

Some p53-binding proteins that can function as arbiters of life and death

“…62 Intriguingly a key Pin1 target site at Ser46, which is phosphorylated by p38 MAPK and HIPK2, is central for modulating p53 apoptotic function. 70,71 Pin1-induced conformational change on Ser46 may be needed to reach the p53 dosage necessary for switching on this subset of genes. Alternatively, Pin1 activity could ameliorate occupancy of p53 proapoptotic promoters.…”