Boehme Karen A, Kulikov Roman, Blattner Christine
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, P.O. Box 3640, 76021 Karlsruhe, Germany.
Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7785-90. doi: 10.1073/pnas.0703423105. Epub 2008 May 27.
The p53 protein is one of the major tumor suppressor proteins. In response to DNA damage, p53 is prevented from degradation and accumulates to high levels. Ionizing radiation leads to hypophosphorylation of the p53 ubiquitin ligase Mdm2 at sites where phosphorylation is critical for p53 degradation and to the phosphorylation and activation of Akt/PKB, a kinase that phosphorylates and inhibits GSK-3. GSK-3, which normally phosphorylates Mdm2, is inactivated in response to ionizing radiation. We show that p53 accumulates in lymphoblasts from patients with the hereditary disorder ataxia telangiectasia in response to ionizing radiation despite the absence of a functional ATM kinase. Also, knockdown of ATR did not prevent p53 accumulation in response to ionizing radiation. Instead, p53 stabilization in response to ionizing radiation depended on the inactivation of GSK-3 and the presence of Akt/PKB. Akt/PKB is a target of DNA-PK, a kinase that is activated after ionizing radiation. Correspondingly, down-regulation of DNA-PK prevented phosphorylation of Akt/PKB and GSK-3 after ionizing radiation and strongly reduced the accumulation of p53. We therefore propose a signaling cascade for the regulation of p53 in response to ionizing radiation that involves activation of DNA-PK and Akt/PKB and inactivation of GSK-3 and Mdm2.
p53蛋白是主要的肿瘤抑制蛋白之一。响应DNA损伤时，p53的降解被阻止并积累至高水平。电离辐射导致p53泛素连接酶Mdm2在对p53降解至关重要的磷酸化位点发生低磷酸化，并导致Akt/PKB（一种磷酸化并抑制GSK-3的激酶）的磷酸化和激活。通常使Mdm2磷酸化的GSK-3在响应电离辐射时失活。我们发现，尽管缺乏功能性的ATM激酶，但患有遗传性疾病共济失调毛细血管扩张症的患者的成淋巴细胞在响应电离辐射时p53仍会积累。此外，敲低ATR并不能阻止p53在响应电离辐射时的积累。相反，p53在响应电离辐射时的稳定依赖于GSK-3的失活和Akt/PKB的存在。Akt/PKB是DNA-PK的一个靶点，DNA-PK是一种在电离辐射后被激活的激酶。相应地，DNA-PK的下调阻止了电离辐射后Akt/PKB和GSK-3的磷酸化，并大大减少了p53的积累。因此，我们提出了一个响应电离辐射调节p53的信号级联反应，该反应涉及DNA-PK和Akt/PKB的激活以及GSK-3和Mdm2的失活。
