Regulation of TopBP1 oligomerization by Akt/PKB for cell survival
Regulation of TopBP1 oligomerization by Akt/PKB for cell survival
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DOI：
10.1038/sj.emboj.7601355
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发表时间：
2006-10-18
期刊：
影响因子：
11.4
通讯作者：
Lin, Weei-Chin
中科院分区：
文献类型：
--
作者：
Liu, Kang;Paik, Jason C.;Lin, Weei-Chin
E2 F1介导的细胞凋亡的调节对于适当的细胞生长是必不可少的。这种控制需要TopBP 1，一种含有BRCT（BRCA 1羧基末端）结构域的蛋白，它与E2 F1相互作用，但不与其他E2 F相互作用，并抑制其促凋亡活性。我们现在发现TopBP 1对E2 F1的调节涉及磷酸肌醇3-激酶（PI 3 K）-Akt信号通路，并且不依赖于口袋蛋白。Akt在体外和体内磷酸化TopBP 1。Akt的磷酸化通过其第七和第八BRCT结构域诱导TopBP 1的寡聚化。Akt依赖性寡聚化对于TopBP 1与E2 F1相互作用和抑制E2 F1至关重要。Akt磷酸化也是TopBP 1和Miz 1或HPV 16 E2之间相互作用以及Miz 1转录活性抑制所必需的，这表明TopBP 1寡聚化在转录因子控制中的一般作用。总之，这项研究定义了一种新的途径，涉及PI 3 K-Akt TopBP 1特异性控制E2 F1细胞凋亡，与细胞周期蛋白-Cdk-Rb的E2 F活动的一般控制平行。
Regulation of E2F1-mediated apoptosis is essential for proper cellular growth. This control requires TopBP1, a BRCT (BRCA1 carboxyl-terminal) domain-containing protein, which interacts with E2F1 but not other E2Fs and represses its proapoptotic activity. We now show that the regulation of E2F1 by TopBP1 involves the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, and is independent of pocket proteins. Akt phosphorylates TopBP1 in vitro and in vivo. Phosphorylation by Akt induces oligomerization of TopBP1 through its seventh and eighth BRCT domains. The Akt-dependent oligomerization is crucial for TopBP1 to interact with and repress E2F1. Akt phosphorylation is also required for interaction between TopBP1 and Miz1 or HPV16 E2, and repression of Miz1 transcriptional activity, suggesting a general role for TopBP1 oligomerization in the control of transcription factors. Together, this study defines a novel pathway involving PI3K-Akt TopBP1 for specific control of E2F1 apoptosis, in parallel with cyclin-Cdk-Rb for general control of E2F activities.