Argininosuccinate synthase 1 is an intrinsic Akt repressor transactivated by p53.
Argininosuccinate synthase 1 is an intrinsic Akt repressor transactivated by p53.
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DOI：
10.1126/sciadv.1603204
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发表时间：
2017-05
期刊：
影响因子：
13.6
通讯作者：
Matsuda K
中科院分区：
文献类型：
--
作者：
Miyamoto T;Lo PHY;Saichi N;Ueda K;Hirata M;Tanikawa C;Matsuda K
ASS 1是p53和Akt之间的桥梁。转录因子p53是一个内在的肿瘤抑制系统的核心，该系统对不同程度的压力输入做出反应，并且在大多数人类癌症中被解除调节。p53在维持细胞适应性和保真度方面发挥作用，调节一组适当的靶基因以响应细胞应激。然而，对这一计划的全面了解尚未完成。我们发现，在精氨酸从头合成途径中的瓜氨酸-天冬氨酸连接酶-此外，我们发现X射线照射促进了P53+/+小鼠中Ass 1的全身诱导，同时增加了血浆精氨酸水平，但在P53−/−小鼠中没有。值得注意的是，由于小肠隐窝中的细胞凋亡增加，Ass 1 +/−小鼠表现出对全身照射的超敏反应。对使用CRISPR（成簇的规则间隔短回文重复序列）-Cas9（CRISPR相关9）系统产生的ASS 1缺陷细胞的分析表明，ASS 1在限制Akt磷酸化方面起着关键作用。此外，由于ASS 1缺失导致的Akt的异常激活破坏了基因毒性应激下Akt介导的细胞存活信号传导活性。在这些结果的基础上，我们证明了p53诱导了一个内在的Akt阻遏物，ASS 1，并且ASS 1表达的扰动使细胞对遗传毒性应激敏感。我们的发现揭示了p53在Akt信号调节中的新功能，并揭示了p53，ASS 1和Akt是如何相互关联的。
ASS1 bridges a gap between p53 and Akt. The transcription factor p53 is at the core of a built-in tumor suppression system that responds to varying degrees of stress input and is deregulated in most human cancers. Befitting its role in maintaining cellular fitness and fidelity, p53 regulates an appropriate set of target genes in response to cellular stresses. However, a comprehensive understanding of this scheme has not been accomplished. We show that argininosuccinate synthase 1 (ASS1), a citrulline-aspartate ligase in de novo arginine synthesis pathway, was directly transactivated by p53 in response to genotoxic stress, resulting in the rearrangement of arginine metabolism. Furthermore, we found that x-ray irradiation promoted the systemic induction of Ass1 and concomitantly increased plasma arginine levels in p53+/+ mice but not in p53−/− mice. Notably, Ass1+/− mice exhibited hypersensitivity to whole-body irradiation owing to increased apoptosis in the small intestinal crypts. Analyses of ASS1-deficient cells generated using the CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 (CRISPR-associated 9) system revealed that ASS1 plays a pivotal role in limiting Akt phosphorylation. In addition, aberrant activation of Akt resulting from ASS1 loss disrupted Akt-mediated cell survival signaling activity under genotoxic stress. Building on these results, we demonstrated that p53 induced an intrinsic Akt repressor, ASS1, and the perturbation of ASS1 expression rendered cells susceptible to genotoxic stress. Our findings uncover a new function of p53 in the regulation of Akt signaling and reveal how p53, ASS1, and Akt are interrelated to each other.