ΔNp63α down-regulates c-Myc modulator MM1 via E3 ligase HERC3 in the regulation of cell senescence
ΔNp63α down-regulates c-Myc modulator MM1 via E3 ligase HERC3 in the regulation of cell senescence
复制标题
αNp63α 通过 E3 连接酶 HERC3 下调 c-Myc 调节剂 MM1 调节细胞衰老
DOI：
10.1038/s41418-018-0132-5
复制
发表时间：
2018-12-01
影响因子：
12.4
通讯作者：
Li, Chenghua
中科院分区：
文献类型：
--
作者：
Chen, Yonglong;Li, Yimin;Li, Chenghua
p63 和 c-Myc 是控制细胞周期和细胞衰老相关基因的关键转录因子。我们之前报道过 p63 α 可以破坏 MM1 蛋白的稳定性，从而解除 c-Myc 的抑制，从而导致细胞周期进展和肿瘤发生。然而，如何促进 MM1 的蛋白酶体降解仍不清楚。在本研究中，我们鉴定了一种新型 E3 连接酶 HERC3，它可以介导 MM1 泛素化并促进其蛋白酶体依赖性降解。我们发现 Delta Np63 α 转录上调 HERC3，HERC3 的敲低消除了 Delta Np63 α 诱导的 MM1 下调。 MM1 的过表达或 HERC3 的消除都会诱导细胞衰老，而 MM1 的敲低则可以挽救由 Delta Np63 α 或 HERC3 缺陷诱导的细胞衰老，这表明 Delta Np63 α/HERC3/MM1/c-Myc 轴参与了细胞衰老的调节。此外，我们的 Oncomine 分析表明 Delta Np63 α/HERC3/MM1/c-Myc 轴在浸润性乳腺癌中被激活。总之，我们的数据阐明了调节细胞衰老的新轴：Delta Np63 α 刺激 E3 连接酶 HERC3 的转录，HERC3 介导 c-Myc 调节剂 MM1 泛素化并将其靶向蛋白酶体降解；随后，c-Myc 被 Delta Np63 α 去抑制，从而通过该轴调节细胞衰老。我们的工作为 p63 和 c-Myc 之间的串扰提供了新的解释，也为 Delta Np63 α 控制的细胞衰老和肿瘤发生提供了新的线索。
p63 and c-Myc are key transcription factors controlling genes involved in the cell cycle and cellular senescence. We previously reported that p63 alpha can destabilize MM1 protein to derepress c-Myc, resulting in cell cycle progress and tumorigenesis. However, how the proteasomal degradation of MM1 is facilitated remains unclear. In the present study, we identified a novel E3 ligase, HERC3, which can mediate ubiquitination of MM1 and promote its proteasome-dependent degradation. We found that Delta Np63 alpha transcriptionally up-regulates HERC3 and knockdown of HERC3 abrogates Delta Np63 alpha-induced down-regulation of MM1. Either overexpression of MM1 or ablation of HERC3 induces cell senescence, while knockdown of MM1 rescues cell senescence induced by deficiency of either Delta Np63 alpha or HERC3, implicating the involvement of the Delta Np63 alpha/HERC3/MM1/c-Myc axis in the modulation of cell senescence. Additionally, our Oncomine analysis indicates activation of the Delta Np63 alpha/HERC3/MM1/c-Myc axis in invasive breast carcinoma. Together, our data illuminate a novel axis regulating cell senescence: Delta Np63 alpha stimulates transcription of E3 ligase HERC3, which mediates ubiquitination of c-Myc modulator MM1 and targets it to proteasomal degradation; subsequently, c-Myc is derepressed by Delta Np63 alpha, thereby cell senescence is modulated by this axis. Our work provides a new interpretation of crosstalk between p63 and c-Myc, and also sheds new light on Delta Np63 alpha-controlled cell senescence and tumorigenesis.