p53 依赖的 G1 DNA 损伤反应
中文名称
通路描述
大多数由损伤诱导的 p53 修饰依赖于 ATM 激酶。ATM 与 p53 之间的第一个联系是基于早期研究得出的，这些研究指出，AT 细胞在暴露于 IR 后表现出 p53 的降低和延迟诱导（Kastan 等，1992 和 Khanna 和 Lavin，1993）。在正常条件下，p53 是一种短寿命蛋白。MDM2 蛋白通常与 p53 相互作用（Haupt 等，1997 和 Kubbutat 等，1997），并利用其 E3 泛素连接酶活性，将 p53 转运至细胞质，介导其泛素 - 蛋白酶体机器中的降解。在检测到 DNA 损伤后，ATM 激酶介导 Mdm2 蛋白的磷酸化，以阻止其与 p53 的相互作用。此外，由 ATM 激酶和其他由 ATM 激酶激活的激酶在多个位点磷酸化 p53，稳定并激活 p53 蛋白。p53 蛋白激活细胞周期依赖性激酶抑制物 p21 的转录。p21 使 CyclinE:Cdk2 复合物失活，阻止细胞进入 S 期，导致 G1 阻滞。在严重条件下，细胞可能发生凋亡。
英文描述
p53-Dependent G1 DNA Damage Response Most of the damage-induced modifications of p53 are dependent on the ATM kinase. The first link between ATM and p53 was predicted based on the earlier studies that showed that AT cells exhibit a reduced and delayed induction of p53 following exposure to IR (Kastan et al, 1992 and Khanna and Lavin, 1993).Under normal conditions, p53 is a short-lived protein. The MDM2 protein, usually interacts with p53 (Haupt et al, 1997 and Kubbutat et al, 1997), and by virtue of its E3 ubiquitin ligase activity, shuttles p53 to the cytoplasm and mediates its degradation by the ubiquitin-proteasome machinery. Upon detection of DNA damage, the ATM kinase mediates the phosphorylation of the Mdm2 protein to block its interaction with p53. Also, phosphorylation of p53 at multiple loci, by the ATM kinase and by other kinases activated by the ATM kinase, stabilizes and activates the p53 protein.The p53 protein activates the transcription of cyclin-dependent kinase inhibitor, p21. p21 inactivates the CyclinE:Cdk2 complexes, and prevent entry of the cell into S phase, leading to G1 arrest. Under severe conditions, the cell may undergo apoptosis.
所含基因
7 个基因