University of Maryland, Marlene & Stewart Greenebaum Cancer Center, Department of Medicine, Baltimore, Maryland 21201, USA.
Nat Commun. 2011 Jul 19;2:402. doi: 10.1038/ncomms1404.
Distinct oncogenic signalling cascades have been associated with non-Hodgkin lymphoma. ERK1/2 signalling elicits both transcriptional and post-transcriptional effects through phosphorylation of numerous substrates. Here we report a novel molecular relationship between ERK1/2 and CHK2, a protein kinase that is a key mediator of the DNA damage checkpoint that responds to DNA double-strand breaks. Our studies are the first to demonstrate the co-localization and overexpression of ERK1/2 and CHK2 in diffuse large B-cell lymphoma (DLBCL). The physical interaction between ERK and CHK2 was highly dependent on phosphorylated Thr 68 of CHK2. Concurrent administration of an ERK inhibitor enhances the antitumour activity of CHK2 inhibition in both a human DLBCL xenograft model as well as primary human DLBCL cells. Our data suggest a functional interaction between ERK and CHK2 and support the potential combined therapeutic targeting of ERK and CHK2 in human DLBCL.
不同的致癌信号通路与非霍奇金淋巴瘤有关。ERK1/2 信号通过磷酸化众多底物引发转录和转录后效应。在这里，我们报告了 ERK1/2 和 CHK2 之间的一种新的分子关系，CHK2 是一种蛋白激酶，是对 DNA 双链断裂做出反应的 DNA 损伤检查点的关键介质。我们的研究首次证明了 ERK1/2 和 CHK2 在弥漫性大 B 细胞淋巴瘤（DLBCL）中的共定位和过表达。ERK 和 CHK2 之间的物理相互作用高度依赖于 CHK2 的磷酸化 Thr68。ERK 抑制剂的同时给药增强了 ERK 抑制在人 DLBCL 异种移植模型以及原代人 DLBCL 细胞中的抗肿瘤活性。我们的数据表明 ERK 和 CHK2 之间存在功能相互作用，并支持在人类 DLBCL 中联合靶向 ERK 和 CHK2 的潜在治疗方法。
