PML enhances the regulation of p53 by CK1 in response to DNA damage

Abstract

In response to stress, p53 is accumulated and activated to induce appropriate growth inhibitory responses. This requires the release of p53 from the constraints of its negative regulators Mdm2 and Mdm4. A key event in this dissociation is the phosphorylation of p53 at threonine residue (Thr18) within the Mdm2/4-binding domain. Casein kinase 1 (CK1) plays a major role in this phosphorylation. The promyelocytic leukemia protein (PML) regulates certain modifications of p53 in response to DNA damage. Here, we investigated the role of PML in the regulation of Thr18 phosphorylation. We found that PML enhances Thr18 phosphorylation of endogenous p53 in response to stress. On DNA damage, CK1 accumulates in the cell, with a proportion concentrated in the nucleus together with p53 and PML. Furthermore, CK1 interacts with endogenous p53 and PML, and this interaction is enhanced by genotoxic stress. Inhibition of CK1 impairs the protection of p53 by PML from Mdm2-mediated degradation. Our findings support a role for PML in the regulation of p53 by CK1. We propose that following DNA damage, PML facilitates Thr18 phosphorylation by recruiting p53 and CK1 into PML nuclear bodies, thereby protecting p53 from inhibition by Mdm2, leading to p53 activation.

DNA Damage Induces the Accumulation of Tiam1 by Blocking β-TrCP-dependent Degradation

“…Previous studies have reported that CK1␦ is recruited into the nucleus in response to doxorubicin treatment (32,52). Drosophila CK1␣ can also translocate into the nucleus, accompanied by high kinase activity after irradiation (53).…”

Recent advances in p53 research: an interdisciplinary perspective

“…33 Another protein, previously shown to inhibit MDM2-mediated p53 degradation, the promyelocytic leukemia protein, was shown to induce the phosphorylation of p53 on Thr18 and Ser20 (two residues located in the Mdm2-binding site) by CK1 and CHEK2, respectively, which induced p53 accumulation and nuclear relocalization. 34 As for PIN1, promyelocytic leukemia protein also interacted with some p53 mutants. Indeed, promyelocytic leukemia protein was shown to regulate the phosphorylation of p.R248W mutant upon stress, suggesting that promyelocytic leukemia protein may enhance the activity of both wild-type and mutant p53.…”

Casein kinase 1 regulates human hypoxia-inducible factor HIF-1

“…This is consistent with observations concerning the effect of CK1 isoforms on the activity of the p53 tumor suppressor protein. Upon cell stress, CK1 phosphorylates p53 in its N-terminal region, weakens the interaction with MDM2 and, therefore, stabilizes and activates p53 function (Alsheich-Bartok et al, 2008;Knippschild et al, 1997;Sakaguchi et al, 2000).…”