Nerve growth factor receptor negates the tumor suppressor p53 as a feedback regulator
Nerve growth factor receptor negates the tumor suppressor p53 as a feedback regulator
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神经生长因子受体否定肿瘤抑制因子 p53 作为反馈调节剂
DOI：
10.7554/elife.15099
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发表时间：
2016-06-10
期刊：
影响因子：
7.7
通讯作者：
Lu, Hua
中科院分区：
文献类型：
--
作者：
Zhou, Xiang;Hao, Qian;Lu, Hua
癌症的发生和进展通常是由于 p53 失活所致。在这里，我们推出了作为新型 p53 灭活剂的神经生长因子受体（NGFR、p75NTR 或 CD271）。 p53 激活 NGFR 转录，而 NGFR 通过促进 MDM2 介导的泛素依赖性蛋白水解作用以及直接与其中央 DNA 结合结构域结合并阻止其 DNA 结合活性来失活 p53。相反，NGFR 消除会激活 p53，从而诱导细胞凋亡、减弱存活率并降低癌细胞的克隆形成能力，并使人类癌细胞对诱导 p53 的化疗药物敏感并抑制小鼠异种移植肿瘤的生长。 NGFR 在人类胶质母细胞瘤中高表达，其基因经常在野生型 p53 乳腺癌中扩增。总而言之，我们的结果表明癌症劫持 NGFR 作为 p53 的致癌抑制剂。
Cancer develops and progresses often by inactivating p53. Here, we unveil nerve growth factor receptor (NGFR, p75NTR or CD271) as a novel p53 inactivator. p53 activates NGFR transcription, whereas NGFR inactivates p53 by promoting its MDM2-mediated ubiquitin-dependent proteolysis and by directly binding to its central DNA binding domain and preventing its DNA-binding activity. Inversely, NGFR ablation activates p53, consequently inducing apoptosis, attenuating survival, and reducing clonogenic capability of cancer cells, as well as sensitizing human cancer cells to chemotherapeutic agents that induce p53 and suppressing mouse xenograft tumor growth. NGFR is highly expressed in human glioblastomas, and its gene is often amplified in breast cancers with wild type p53. Altogether, our results demonstrate that cancers hijack NGFR as an oncogenic inhibitor of p53.