Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):11005-10. doi: 10.1073/pnas.1308497110. Epub 2013 Jun 13.
Our recent studies suggest a role for the proteasome activator REG (11S regulatory particles, 28-kDa proteasome activator)γ in the regulation of tumor protein 53 (p53). However, the molecular details and in vivo biological significance of REGγ-p53 interplay remain elusive. Here, we demonstrate that REGγ-deficient mice develop premature aging phenotypes that are associated with abnormal accumulation of casein kinase (CK) 1δ and p53. Antibody array analysis led us to identify CK1δ as a direct target of REGγ. Silencing CK1δ or inhibition of CK1δ activity prevented decay of murine double minute (Mdm)2. Interestingly, a massive increase of p53 in REGγ(-/-) tissues is associated with reduced Mdm2 protein levels despite that Mdm2 transcription is enhanced. Allelic p53 haplodeficiency in REGγ-deficient mice attenuated premature aging features. Furthermore, introducing exogenous Mdm2 to REGγ(-/-) MEFs significantly rescues the phenotype of cellular senescence, thereby establishing a REGγ-CK1-Mdm2-p53 regulatory pathway. Given the conflicting evidence regarding the "antiaging" and "proaging" effects of p53, our results indicate a key role for CK1δ-Mdm2-p53 regulation in the cellular aging process. These findings reveal a unique model that mimics acquired aging in mammals and indicates that modulating the activity of the REGγ-proteasome may be an approach for intervention in aging-associated disorders.
我们最近的研究表明，蛋白酶体激活剂 REG（11S 调节颗粒，28kDa 蛋白酶体激活剂）γ 在调节肿瘤蛋白 53（p53）方面发挥作用。然而，REGγ-p53 相互作用的分子细节和体内生物学意义仍不清楚。在这里，我们证明 REGγ 缺陷小鼠表现出早衰表型，与酪蛋白激酶（CK）1δ和 p53 的异常积累有关。抗体阵列分析使我们能够鉴定 CK1δ 为 REGγ 的直接靶标。沉默 CK1δ 或抑制 CK1δ 活性可防止鼠双微体（Mdm）2 降解。有趣的是，尽管 Mdm2 转录增强，但 REGγ(-/-)组织中大量增加的 p53与降低的 Mdm2 蛋白水平有关。REGγ 缺陷小鼠的等位基因 p53 单倍体缺陷减轻了早衰特征。此外，将外源性 Mdm2 引入 REGγ(-/-) MEFs 可显著挽救细胞衰老表型，从而建立了 REGγ-CK1-Mdm2-p53 调控途径。鉴于关于 p53 的“抗衰老”和“促衰老”作用的相互矛盾的证据，我们的结果表明 CK1δ-Mdm2-p53 调节在细胞衰老过程中起着关键作用。这些发现揭示了一个独特的模型，模拟了哺乳动物获得性衰老，并表明调节 REGγ-蛋白酶体的活性可能是干预与衰老相关疾病的一种方法。
