PML enhances the regulation of p53 by CK1 in response to DNA damage.
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.
Alsheich-Bartok
O
O
Department of Immunology, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
Haupt
S
S
Alkalay-Snir
I
I
Saito
S
S
Appella
E
E
Haupt
Y
Y
D021581:Active Transport, Cell Nucleus; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D047389:Casein Kinase I / Q000502:physiology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D009363:Neoplasm Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D010087:Oxides / Q000494:pharmacology; D010766:Phosphorylation; D000071156:Promyelocytic Leukemia Protein; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology; D013912:Threonine / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D001152:Arsenicals; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D013912:Threonine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D047389:Casein Kinase I; D000077237:Arsenic Trioxide