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NatB regulates Rb mutant cell death and tumor growth by modulating EGFR/MAPK signaling through the N-end rule pathways.
PLOS Genetics ( IF 4.0 ) Pub Date : 2020-06-19 , DOI: 10.1371/journal.pgen.1008863
Zhentao Sheng 1 , Wei Du 1
Affiliation  

Inactivation of the Rb tumor suppressor causes context-dependent increases in cell proliferation or cell death. In a genetic screen for factors that promoted Rb mutant cell death in Drosophila, we identified Psid, a regulatory subunit of N-terminal acetyltransferase B (NatB). We showed that NatB subunits were required for elevated EGFR/MAPK signaling and Rb mutant cell survival. We showed that NatB regulates the posttranscriptional levels of the highly conserved pathway components Grb2/Drk, MAPK, and PP2AC but not that of the less conserved Sprouty. Interestingly, NatB increased the levels of positive pathway components Grb2/Drk and MAPK while decreased the levels of negative pathway component PP2AC, which were mediated by the distinct N-end rule branch E3 ubiquitin ligases Ubr4 and Cnot4, respectively. These results suggest a novel mechanism by which NatB and N-end rule pathways modulate EGFR/MAPK signaling by inversely regulating the levels of multiple conserved positive and negative pathway components. As inactivation of Psid blocked EGFR signaling-dependent tumor growth, this study raises the possibility that NatB is potentially a novel therapeutic target for cancers dependent on deregulated EGFR/Ras signaling.



中文翻译:

NatB 通过 N 端规则通路调节 EGFR/MAPK 信号传导来调节 Rb 突变细胞死亡和肿瘤生长。

Rb 肿瘤抑制因子的失活会导致细胞增殖或细胞死亡的情况依赖性增加。在对促进果蝇Rb 突变细胞死亡的因素进行遗传筛选时,我们鉴定了 Psid,它是 N 末端乙酰转移酶 B (NatB) 的调节亚基。我们发现 NatB 亚基是 EGFR/MAPK 信号传导增强和 Rb 突变细胞存活所必需的。我们发现 NatB 调节高度保守的通路组件 Grb2/Drk、MAPK 和 PP2AC 的转录后水平,但不调节不太保守的 Sprouty 的转录后水平。有趣的是,NatB 增加了正通路成分 Grb2/Drk 和 MAPK 的水平,同时降低了负通路成分 PP2AC 的水平,这分别由不同的 N 端规则分支 E3 泛素连接酶 Ubr4 和 Cnot4 介导。这些结果提出了一种新机制,NatB 和 N 端规则通路通过反向调节多个保守的正负通路成分的水平来调节 EGFR/MAPK 信号传导。由于 Psid 失活可阻断 EGFR 信号传导依赖性肿瘤生长,因此这项研究提出了 NatB 可能成为依赖于 EGFR/Ras 信号传导失调的癌症的新治疗靶点的可能性。

更新日期:2020-06-19
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