Open AccessA TRAIL receptor-dependent synthetic lethal relationship between MYC activation and GSK3β/FBW7 loss of function
Author(s) -
Sabine Rottmann,
Yan Wang,
Marc Nasoff,
Quinn L. Deveraux,
Kim Quon
Publication year - 2005
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0505114102
Subject(s) - gsk 3 , ubiquitin ligase , gene silencing , biology , cancer research , apoptosis , kinase , gsk3b , microbiology and biotechnology , small interfering rna , signal transduction , receptor , phosphorylation , glycogen synthase , ubiquitin , gene , rna , biochemistry
TheMYC protooncogene is frequently deregulated in human cancers. Here, by screening a kinase-directed library of small inhibitory RNAs, we identify glycogen synthase kinase 3β (GSK3 β) 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 ofGSK3 β prevents phosphorylation of MYC on T58, thereby inhibiting recognition of MYC by the E3 ubiquitin ligase component FBW7. Attenuating the GSK3β–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 apoptosisin vitro andin vivo . These results identify GSK3β and FBW7 as potential cancer therapeutic targets and MYC as a critical substrate in the GSK3β 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.