Rottmann Sabine, Wang Yan, Nasoff Marc, Deveraux Quinn L, Quon Kim C
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15195-200. doi: 10.1073/pnas.0505114102. Epub 2005 Oct 6.
The MYC protooncogene is frequently deregulated in human cancers. Here, by screening a kinase-directed library of small inhibitory RNAs, we identify glycogen synthase kinase 3beta (GSK3beta) as a gene whose inactivation potentiates TNF-related apoptosis-inducing ligand death receptor-mediated apoptosis specifically in MYC-overexpressing cells. Small inhibitory RNA-induced silencing of GSK3beta prevents phosphorylation of MYC on T58, thereby inhibiting recognition of MYC by the E3 ubiquitin ligase component FBW7. Attenuating the GSK3beta-FBW7 axis results in stabilization of MYC, up-regulation of surface levels of the TNF-related apoptosis-inducing ligand death receptor 5, and potentiation of death receptor 5-induced apoptosis in vitro and in vivo. These results identify GSK3beta and FBW7 as potential cancer therapeutic targets and MYC as a critical substrate in the GSK3beta survival-signaling pathway. The results also demonstrate paradoxically that MYC-expressing tumors might be treatable by drug combinations that increase rather than decrease MYC oncoprotein function.
MYC原癌基因在人类癌症中经常发生失调。在此，通过筛选一个激酶导向的小干扰RNA文库，我们确定糖原合酶激酶3β（GSK3β）是一个基因，其失活能增强肿瘤坏死因子相关凋亡诱导配体死亡受体介导的凋亡，且这种增强作用特异性地发生在MYC过表达的细胞中。小干扰RNA诱导的GSK3β沉默可阻止MYC在T58位点的磷酸化，从而抑制E3泛素连接酶组分FBW7对MYC的识别。减弱GSK3β - FBW7轴会导致MYC的稳定、肿瘤坏死因子相关凋亡诱导配体死亡受体5表面水平的上调，以及体外和体内死亡受体5诱导凋亡的增强。这些结果确定GSK3β和FBW7为潜在的癌症治疗靶点，并确定MYC是GSK3β生存信号通路中的关键底物。这些结果还自相矛盾地表明，表达MYC的肿瘤可能可通过增加而非降低MYC癌蛋白功能的药物组合来治疗。
