Centre National de la Recherche Scientifique-Unité Mixte de Recherche 8113, Laboratoire de Biotechnologie et Pharmacologie génétique Appliquée, École Normale Supérieure, Cachan, France.
Nat Med. 2011 Dec 11;18(1):91-9. doi: 10.1038/nm.2546.
Screening for genes that reprogram cancer cells for the tumor reversion switch identified TCTP (encoding translationally controlled tumor protein) as a crucial regulator of apoptosis. Here we report a negative feedback loop between P53 and TCTP. TCTP promotes P53 degradation by competing with NUMB for binding to P53-MDM2-containing complexes. TCTP inhibits MDM2 auto-ubiquitination and promotes MDM2-mediated ubiquitination and degradation of P53. Notably, Tctp haploinsufficient mice are sensitized to P53-dependent apoptosis. In addition, P53 directly represses TCTP transcription. In 508 breast cancers, high-TCTP status associates with poorly differentiated, aggressive G3-grade tumors, predicting poor prognosis (P < 0.0005). Tctp knockdown in primary mammary tumor cells from ErbB2 transgenic mice results in increased P53 expression and a decreased number of stem-like cancer cells. The pharmacological compounds sertraline and thioridazine increase the amount of P53 by neutralizing TCTP's action on the MDM2-P53 axis. This study links TCTP and P53 in a previously unidentified regulatory circuitry that may underlie the relevance of TCTP in cancer.
筛选用于肿瘤逆转开关的基因以重新编程癌细胞，确定 TCTP（编码翻译控制肿瘤蛋白）为细胞凋亡的关键调节因子。在这里，我们报告了 P53 和 TCTP 之间的负反馈回路。TCTP 通过与 NUMB 竞争与 P53-MDM2 复合物结合，促进 P53 的降解。TCTP 抑制 MDM2 自身泛素化，并促进 MDM2 介导的 P53 泛素化和降解。值得注意的是，Tctp 杂合不足的小鼠对 P53 依赖性细胞凋亡敏感。此外，P53 直接抑制 TCTP 的转录。在 508 例乳腺癌中，高 TCTP 状态与分化不良、侵袭性 G3 级肿瘤相关，预示预后不良（P<0.0005）。在 ErbB2 转基因小鼠的原发性乳腺肿瘤细胞中敲低 Tctp 导致 P53 表达增加和干细胞样癌细胞数量减少。药物化合物舍曲林和硫利达嗪通过中和 TCTP 对 MDM2-P53 轴的作用增加 P53 的量。这项研究将 TCTP 和 P53 联系在一个以前未被识别的调节回路中，该回路可能是 TCTP 在癌症中相关性的基础。
