A RelA(p65) Thr505 phospho-site mutation reveals an important mechanism regulating NF-κB-dependent liver regeneration and cancer.
A RelA(p65) Thr505 phospho-site mutation reveals an important mechanism regulating NF-κB-dependent liver regeneration and cancer.
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RELA（P65）THR505磷酸位点突变揭示了调节NF-κB依赖性肝脏再生和癌症的重要机制。
DOI：
10.1038/onc.2015.526
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发表时间：
2016-09-01
期刊：
影响因子：
8
通讯作者：
Perkins ND
中科院分区：
文献类型：
--
作者：
Moles A;Butterworth JA;Sanchez A;Hunter JE;Leslie J;Sellier H;Tiniakos D;Cockell SJ;Mann DA;Oakley F;Perkins ND
核因子（NF）-κB亚基的翻译后修饰提供了一种机制，可以对诱导该途径的许多刺激进行差异调节。然而，这些修饰的生理意义在很大程度上是未知的，并且仍然不清楚这些修饰是否在体内NF-κB的正常和病理功能中具有关键作用。其中，RelA（p65）Thr 505残基的磷酸化被描述为细胞系中NF-κB活性的重要调节剂，但其生理学意义尚不清楚。因此，为了更多地了解该途径在体内的作用，我们产生了具有RelA T505 A突变的敲入小鼠。与RelA基因敲除小鼠不同，RelA T505 A小鼠发育正常，但在肝脏部分肝切除术或四氯化碳（CCl 4）治疗引起的损伤后表现出异常的肝细胞增殖。与这些作用一致，RelA T505 A小鼠在肝细胞癌的N-亚硝基二乙胺模型中表现出较早的癌症发作。这些数据揭示了控制肝脏中NF-κB功能的关键途径，其作用是抑制RelA的促肿瘤活性。
Post-translational modifications of nuclear factor (NF)-κB subunits provide a mechanism to differentially regulate their activity in response to the many stimuli that induce this pathway. However, the physiological significance of these modifications is largely unknown, and it remains unclear if these have a critical role in the normal and pathological functions of NF-κB in vivo. Among these, phosphorylation of the RelA(p65) Thr505 residue has been described as an important regulator of NF-κB activity in cell lines, but its physiological significance was not known. Therefore, to learn more about the role of this pathway in vivo, we generated a knockin mouse with a RelA T505A mutation. Unlike RelA knockout mice, the RelA T505A mice develop normally but exhibit aberrant hepatocyte proliferation following liver partial hepatectomy or damage resulting from carbon tetrachloride (CCl4) treatment. Consistent with these effects, RelA T505A mice exhibit earlier onset of cancer in the N-nitrosodiethylamine model of hepatocellular carcinoma. These data reveal a critical pathway controlling NF-κB function in the liver that acts to suppress the tumour-promoting activities of RelA.