PML enhances the regulation of p53 by CK1 in response to DNA damage
PML enhances the regulation of p53 by CK1 in response to DNA damage
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DOI：
10.1038/sj.onc.1211036
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发表时间：
2008-06-01
期刊：
影响因子：
8
通讯作者：
Haupt, Y.
中科院分区：
文献类型：
--
作者：
Alsheich-Bartok, O.;Haupt, S.;Haupt, Y.
在应激反应中，p53被积累和激活以诱导适当的生长抑制反应。这需要p53从负调控因子Mdm2和Mdm4的约束中释放出来。这种解离的一个关键事件是p53在mdm2 /4结合域中苏氨酸残基（Thr18）的磷酸化。酪蛋白激酶1 （CK1）在这一磷酸化过程中起主要作用。早幼粒细胞白血病蛋白（PML）调控某些模式。p53的阳离子对DNA损伤的反应在这里，我们研究了PML在Thr18磷酸化调控中的作用。我们发现PML在应激反应中增强了内源性p53的Thr18磷酸化。DNA损伤时，CK1在细胞内积累，并与p53和PML一起集中在细胞核中。此外，CK1与内源性p53和PML相互作用，这种相互作用在基因毒性应激下增强。CK1的抑制削弱了PML对p53的保护作用，使其免受mdm2介导的降解。我们的研究结果支持PML在CK1调控p53中的作用。我们认为，在DNA损伤后，PML通过将p53和CK1招募到PML核小体中，促进Thr18磷酸化，从而保护p53免受Mdm2的抑制，从而导致p53活化。
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 modi. cations 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.