ATM Augments Nuclear Stabilization of DYRK2 by Inhibiting MDM2 in the Apoptotic Response to DNA Damage
ATM Augments Nuclear Stabilization of DYRK2 by Inhibiting MDM2 in the Apoptotic Response to DNA Damage
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DOI：
10.1074/jbc.m109.042341
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发表时间：
2010-02-12
影响因子：
4.8
通讯作者：
Yoshida, Kiyotsugu
中科院分区：
文献类型：
--
作者：
Taira, Naoe;Yamamoto, Hiroyuki;Yoshida, Kiyotsugu
肿瘤抑制因子p53是一种转录因子，调节细胞周期、DNA修复、衰老和细胞凋亡以响应DNA损伤。p53在Ser-46的磷酸化对于凋亡性细胞死亡的承诺是必不可少的。先前的研究表明，在暴露于遗传毒性应激时，DYRK 2易位到细胞核中并磷酸化p53的Ser-46，从而诱导细胞凋亡。然而，很少有人知道负责DYRK 2的细胞内控制的机制。在这里，我们展示了DYRK 2的N-末端结构域的功能性核定位信号。在正常条件下，细胞核而不是细胞质DYRK 2被MDM 2泛素化，导致其组成性降解。在蛋白酶体抑制剂的存在下，我们检测到一个稳定的复合物DYRK 2与MDM 2的核。暴露于遗传毒性应激后，ATM使DYRK 2在Thr-33和Ser-369处磷酸化，这使得DYRK 2能够通过与MDM 2解离而逃避降解，并诱导细胞核中Ser-46处的p53激酶活性。这些发现表明ATM控制DYRK 2响应DNA损伤的稳定性和促凋亡功能。
The tumor suppressor p53 is a transcription factor that regulates cell cycle, DNA repair, senescence, and apoptosis in response to DNA damage. Phosphorylation of p53 at Ser-46 is indispensable for the commitment to apoptotic cell death. A previous study has shown that upon exposure to genotoxic stress, DYRK2 translocates into the nucleus and phosphorylates p53 at Ser-46, thereby inducing apoptosis. However, less is known about mechanisms responsible for intracellular control of DYRK2. Here we show the functional nuclear localization signal at N-terminal domain of DYRK2. Under normal conditions, nuclear and not cytoplasmic DYRK2 is ubiquitinated by MDM2, resulting in its constitutive degradation. In the presence of proteasome inhibitors, we detected a stable complex of DYRK2 with MDM2 at the nucleus. Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. These findings indicate that ATM controls stability and pro-apoptotic function of DYRK2 in response to DNA damage.