NEURL4 regulates the transcriptional activity of tumor suppressor protein p53 by modulating its oligomerization.
NEURL4 regulates the transcriptional activity of tumor suppressor protein p53 by modulating its oligomerization.
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DOI：
10.18632/oncotarget.18699
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发表时间：
2017-09-22
期刊：
影响因子：
--
通讯作者：
Rosa JL
中科院分区：
文献类型：
--
作者：
Cubillos-Rojas M;Schneider T;Bartrons R;Ventura F;Rosa JL
p53是调节与肿瘤抑制相关的重要细胞过程的转录因子，包括诱导衰老、凋亡和DNA修复以及抑制血管生成和细胞迁移。因此，了解调控它的分子机制至关重要。p53四聚化是其活化过程中的关键步骤，而这种寡聚化的调控是重要的控制点。E3泛素连接酶HERC 2通过调节其寡聚化状态来控制p53转录活性。HERC 2相互作用蛋白，如具有六个神经化结构域的衔接子样蛋白NEURL 4也是调节p53活性的候选者。在这里，我们证明了NEURL 4，HERC 2和p53蛋白之间存在相互作用网络。我们报告了NEURL 4和p53之间的功能相互作用，涉及p53的C-末端区域和NEURL 4的神经化结构域3和4。通过这种相互作用，NEURL 4调节p53的转录活性。因此，NEURL 4缺失降低了转录活性，而NEURL 4过表达增加了转录活性。在这两种情况下，p53稳定性不受影响。虽然NEURL 4可以独立于E3泛素连接酶HERC 2与p53相互作用，但我们观察到这两种蛋白都需要调节p53的转录活性。克隆形成试验证实了这种相互作用的功能相关性，观察到NEURL 4过表达导致的细胞生长减少与p53激活导致的细胞周期抑制剂p21增加相关。在这些条件下，NEURL 4激活p53寡聚化。所有这些发现都将NEURL 4确定为p53信号传导的新型调节剂。
p53 is a transcription factor that regulates important cellular processes related to tumor suppression, including induction of senescence, apoptosis, and DNA repair as well as the inhibition of angiogenesis and cell migration. Therefore, it is critical to understand the molecular mechanism that regulates it. p53 tetramerization is a key step in its activation process and the regulation of this oligomerization, an important control point. The E3 ubiquitin ligase HERC2 controls the p53 transcriptional activity by regulation of its oligomerization state. HERC2-interacting proteins such as the adaptor-like protein with six neuralized domains NEURL4 are also candidates to regulate p53 activity. Here, we demonstrate the existence of an interaction network between NEURL4, HERC2 and p53 proteins. We report a functional interaction between NEURL4 and p53, involving the C-terminal region of p53 and the neuralized domains 3 and 4 of NEURL4. Through this interaction, NEURL4 regulates the transcriptional activity of p53. Thus, NEURL4 depletion reduced the transcriptional activity whereas NEURL4 overexpression increased it. In both cases, p53 stability was not affected. Although NEURL4 may interact with p53 independently of the E3 ubiquitin ligase HERC2, we observed that both proteins are needed to regulate the transcriptional activity of p53. Clonogenic assays confirmed the functional relevance of this interaction observing a decrease in cell growth by NEURL4 overexpression correlated to the increase of cellular cycle inhibitor p21 by p53 activation. Under these conditions, NEURL4 activated p53 oligomerization. All these findings identify NEURL4 as a novel regulator of the p53’s signaling.
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