Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia.
Leukemia. 2013 Apr;27(5):1053-62. doi: 10.1038/leu.2012.361. Epub 2012 Dec 11.
Loss of function mutation in FBXW7, an E3 ubiquitin ligase, is associated with good prognosis and early glucocorticoid treatment response in childhood T-cell acute lymphoblastic leukemia (T-ALL) by unknown mechanisms. Here, we show that FBXW7 targets the glucocorticoid receptor α (GRα) for ubiquitylation and proteasomal degradation in a manner dependent on glycogen synthase kinase 3 β-mediated phsophorylation. FBXW7 inactivation caused elevated GRα levels, and enhanced the transcriptional response to glucocorticoids. There was significant enhancement of GR transcriptional responses in FBXW7-deficient cell lines and primary T-ALL samples, in particular, for those pro-apoptotic regulatory proteins, BIM and PUMA. Reduced FBXW7 expression or function promoted glucocorticoid sensitivity, but not sensitivity to other chemotherapeutic agents used in T-ALL. Moreover, this was a general feature of different cancer cell types. Taken together, our work defines GRα as a novel FBXW7 substrate and demonstrates that favorable patient prognosis in T-ALL is associated with FBXW7 mutations due to enhanced GRα levels and steroid sensitivity. These findings suggest that inactivation of FBXW7, a putative tumor suppressor protein, may create a synthetic lethal state in the presence of specific anticancer therapies.
功能丧失性突变 FBXW7，一种 E3 泛素连接酶，通过未知机制与儿童 T 细胞急性淋巴细胞白血病（T-ALL）的良好预后和早期糖皮质激素治疗反应相关。在这里，我们表明 FBXW7 通过糖原合酶激酶 3β介导的磷酸化依赖的方式靶向糖皮质激素受体α（GRα）进行泛素化和蛋白酶体降解。FBXW7 的失活导致 GRα 水平升高，并增强了对糖皮质激素的转录反应。在 FBXW7 缺陷细胞系和原发性 T-ALL 样本中，GR 转录反应得到了显著增强，特别是对于那些促凋亡的调节蛋白 BIM 和 PUMA。降低 FBXW7 的表达或功能促进了糖皮质激素的敏感性，但对 T-ALL 中使用的其他化疗药物没有敏感性。此外，这是不同癌细胞类型的共同特征。总之，我们的工作将 GRα 定义为一种新型 FBXW7 底物，并表明 T-ALL 中患者预后良好与 FBXW7 突变有关，这是由于 GRα 水平升高和类固醇敏感性增强所致。这些发现表明，在存在特定的抗癌治疗时，假定的肿瘤抑制蛋白 FBXW7 的失活可能会产生合成致死状态。
