RITA1 drives the growth of bladder cancer cells by recruiting TRIM25 to facilitate the proteasomal degradation of RBPJ.
RITA1 drives the growth of bladder cancer cells by recruiting TRIM25 to facilitate the proteasomal degradation of RBPJ.
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DOI：
10.1111/cas.15459
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发表时间：
2022-09
期刊：
影响因子：
5.7
通讯作者：
Liu, Zhuowei
中科院分区：
文献类型：
--
作者：
Tang, Huancheng;Li, Xiangdong;Jiang, Lijuan;Liu, Zefu;Chen, Lei;Chen, Jiawei;Deng, Minhua;Zhou, Fangjian;Zheng, Xianchong;Liu, Zhuowei
膀胱癌是世界上最常见的恶性肿瘤之一，但由于其分子机制尚不明确，缺乏有效的靶向治疗。因此，进一步研究介导BC进展的分子机制非常重要。通过对肿瘤组织基因芯片和shRNA文库的筛选，我们发现重组信号结合蛋白RBPJ和微管蛋白相关蛋白1（RITA 1）对BC细胞的生长至关重要。此外，RITA 1在BC组织中异常高表达，也与BC患者的不良预后相关。从机制上讲，我们确定RITA 1招募包含25个三重基序（TRIM 25）的泛素化RBPJ，通过蛋白酶体加速其降解，从而导致Notch 1下游靶点的转录抑制。我们的研究结果表明，RITA 1的异常高表达通过RITA 1/TRIM 25/RBPJ轴驱动BC细胞的生长，RITA 1可能作为BC的有希望的治疗靶点。我们证明RITA 1的异常上调通过抑制Notch 1信号传导对维持BC细胞的生长至关重要。更重要的是，我们首次确定了一种新的机制，即RITA 1招募TRIM 25来泛素化RBPJ，以加速其蛋白酶体降解，从而导致Notch 1下游靶点的转录抑制。
Bladder cancer (BC) is one of the most prevalent malignancies worldwide, but it lacks effective targeted therapy due to its elusive molecular mechanism. Therefore, it is important to further investigate the molecular mechanisms that mediate BC progression. By performing a tumor tissue–based gene microarray and shRNA library screening, we found that recombination signal binding protein for immunoglobulin kappa J region (RBPJ) interacting and tubulin associated 1 (RITA1) is crucial for the growth of BC cells. Moreover, RITA1 is aberrantly highly expressed in BC tissues and is also correlated with poor prognosis in patients with BC. Mechanistically, we determined that RITA1 recruits tripartite motif containing 25 (TRIM25) to ubiquitinate RBPJ to accelerate its degradation via proteasome, which leads to the transcriptional inhibition of Notch1 downstream targets. Our results suggest that aberrant high expression of RITA1 drives the growth of BC cells via the RITA1/TRIM25/RBPJ axis and RITA1 may serve as a promising therapeutic target for BC. We demonstrated that aberrant upregulation of RITA1 is crucial for maintaining the growth of BC cells by inhibiting Notch1 signaling. More importantly, we determined, for the first time, a novel mechanism whereby RITA1 recruits TRIM25 to ubiquitinate RBPJ to accelerate its proteasomal degradation, which leads to the transcriptional inhibition of Notch1 downstream targets.
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影响因子：
11.4
作者：
Wacker, Stephan Armin;Alvarado, Cristobal;Oswald, Franz
通讯作者：
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影响因子：
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DOI：
10.1084/jem.20110198
发表时间：
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期刊：
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DOI：
10.1038/nrg3272
发表时间：
2012-09
期刊：
Nature reviews. Genetics
影响因子：
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影响因子：
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作者：
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