State Key Laboratory of Medical Neurobiology and Pharmacology Research Center, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
J Biol Chem. 2010 Apr 23;285(17):12823-30. doi: 10.1074/jbc.M109.094243. Epub 2010 Feb 2.
G-protein-coupled receptor kinases (GRKs) are an important family of Ser/Thr kinases that specifically phosphorylate and desensitize the activated receptor in response to environmental stimulation. Here we identify p53, a key tumor suppressor, as a novel GRK substrate in vivo, revealing a previously unknown function of GRKs in regulation of genome stability. Knockdown GRK5 in osteosarcoma cells inhibits DNA damage-induced apoptosis via a p53-mediated mechanism. Furthermore, GRK5, but not GRK2 or GRK6, phosphorylates p53 at Thr-55, which promotes the degradation of p53, leading to inhibition of p53-dependent apoptotic response to genotoxic damage. Consistently, the increase of p53 and irradiation-induced apoptosis were observed in GRK5-deficient mice. These results demonstrate GRK5 as a novel kinase of p53, as well as a negative regulator of p53-mediated signal transduction.
G 蛋白偶联受体激酶（GRKs）是 Ser/Thr 激酶家族的重要成员，能够特异性磷酸化和脱敏激活受体，以响应环境刺激。在此，我们鉴定出 p53（一种关键的肿瘤抑制因子）是体内的一种新型 GRK 底物，揭示了 GRKs 在调节基因组稳定性方面的一个先前未知的功能。在骨肉瘤细胞中敲低 GRK5 通过 p53 介导的机制抑制 DNA 损伤诱导的细胞凋亡。此外，GRK5（而非 GRK2 或 GRK6）可使 p53 的 Thr-55 磷酸化，促进 p53 降解，从而抑制 p53 对遗传毒性损伤的依赖型凋亡反应。一致地，在 GRK5 缺陷型小鼠中观察到 p53 的增加和辐照诱导的细胞凋亡。这些结果表明 GRK5 是 p53 的一种新型激酶，也是 p53 介导的信号转导的负调控因子。
