Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK.
Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, UK.
Cell Death Dis. 2018 May 1;9(5):443. doi: 10.1038/s41419-018-0467-3.
Trib2 pseudokinase is involved in the etiology of a number of cancers including leukaemia, melanoma, ovarian, lung and liver cancer. Both high and low Trib2 expression levels correlate with different types of cancer. Elevated Trib2 expression has oncogenic properties in both leukaemia and lung cancer dependent on interactions with proteasome machinery proteins and degradation of transcription factors. Here, we demonstrated that Trib2 deficiency conferred a growth and survival advantage both at steady state and in stress conditions in leukaemia cells. In response to stress, wild type leukaemia cells exited the cell cycle and underwent apoptosis. In contrast, Trib2 deficient leukaemia cells continued to enter mitosis and survive. We showed that Trib2 deficient leukaemia cells had defective MAPK p38 signalling, which associated with a reduced γ-H2Ax and Chk1 stress signalling response, and continued proliferation following stress, associated with inefficient activation of cell cycle inhibitors p21, p16 and p19. Furthermore, Trib2 deficient leukaemia cells were more resistant to chemotherapy than wild type leukaemia cells, having less apoptosis and continued propagation. Trib2 re-expression or pharmacological activation of p38 in Trib2 deficient leukaemia cells sensitised the cells to chemotherapy-induced apoptosis comparable with wild type leukaemia cells. Our data provide evidence for a tumour suppressor role of Trib2 in myeloid leukaemia via activation of p38 stress signalling. This newly identified role indicates that Trib2 may counteract the propagation and chemotherapy resistance of leukaemia cells.
Trib2 假激酶参与多种癌症的发病机制，包括白血病、黑色素瘤、卵巢癌、肺癌和肝癌。高表达和低表达 Trib2 水平都与不同类型的癌症相关。Trib2 的表达水平升高在白血病和肺癌中具有致癌特性，这依赖于与蛋白酶体机制蛋白的相互作用以及转录因子的降解。在这里，我们证明 Trib2 缺失在白血病细胞的稳定状态和应激条件下赋予了生长和存活优势。在应激反应中，野生型白血病细胞退出细胞周期并发生凋亡。相比之下，Trib2 缺失的白血病细胞继续进入有丝分裂并存活。我们表明，Trib2 缺失的白血病细胞存在 MAPK p38 信号通路缺陷，这与 γ-H2Ax 和 Chk1 应激信号反应减少有关，并且在应激后继续增殖，与细胞周期抑制剂 p21、p16 和 p19 的激活效率低下有关。此外，Trib2 缺失的白血病细胞比野生型白血病细胞对化疗更具抵抗力，凋亡较少且持续增殖。在 Trib2 缺失的白血病细胞中重新表达 Trib2 或激活 p38 可使细胞对化疗诱导的凋亡敏感，与野生型白血病细胞相当。我们的数据为 Trib2 在髓性白血病中通过激活 p38 应激信号发挥肿瘤抑制作用提供了证据。这个新发现的作用表明 Trib2 可能会对抗白血病细胞的增殖和化疗耐药性。
