The transcription factor receptor‐interacting protein 140 (RIP140) regulates intestinal homeostasis and tumorigenesis through Wnt signaling. In this study, we investigated its effect on the Notch/HES1 signaling pathway. In colorectal cancer (CRC) cell lines, RIP140 positively regulated HES1 gene expression at the transcriptional level via a recombining binding protein suppressor of hairless (RBPJ)/neurogenic locus notch homolog protein 1 (NICD)‐mediated mechanism. In support of these in vitro data, RIP140 and HES1 expression significantly correlated in mouse intestine and in a cohort of CRC samples, thus supporting the positive regulation of HES1 gene expression by RIP140. Interestingly, when the Notch pathway is fully activated, RIP140 exerted a strong inhibition of HES1 gene transcription controlled by the level of HES1 itself. Moreover, RIP140 directly interacts with HES1 and reversed its mitogenic activity in human CRC cells. In line with this observation, HES1 levels were associated with a better patient survival only when tumors expressed high levels of RIP140. Our data identify RIP140 as a key regulator of the Notch/HES1 signaling pathway, with a dual effect on HES1 gene expression at the transcriptional level and a strong impact on colon cancer cell proliferation.

中文翻译：

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RIP140 调节结肠癌细胞中转录因子 HES1 振荡表达和促有丝分裂活性

转录因子受体相互作用蛋白 140 (RIP140) 通过 Wnt 信号传导调节肠道稳态和肿瘤发生。在本研究中，我们研究了它对 Notch/HES1 信号通路的影响。在结直肠癌 (CRC) 细胞系中，RIP140 呈正向调节HES1通过无毛重组结合蛋白抑制因子 (RBPJ)/神经源性位点缺口同源蛋白 1 (NICD) 介导的机制在转录水平上进行基因表达。为了支持这些体外数据显示，RIP140 和 HES1 表达在小鼠肠道和一组 CRC 样本中显着相关，从而支持HES1RIP140 的基因表达。有趣的是，当Notch通路完全激活时，RIP140对HES1基因转录受HES1本身水平控制。此外，RIP140 直接与 HES1 相互作用并逆转其在人类 CRC 细胞中的有丝分裂活性。与这一观察结果一致，只有当肿瘤表达高水平的 RIP140 时，HES1 水平才与更好的患者生存相关。我们的数据表明 RIP140 是 Notch/HES1 信号通路的关键调节因子，对HES1转录水平上的基因表达对结肠癌细胞增殖有强烈影响。