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Early growth response-1 is a new substrate of the GSK3β-FBXW7 axis

EGR1, a short-lived transcription factor, regulates several biological processes, including cell proliferation and tumor progression. Whether and how EGR1 is regulated by Cullin-RING ligases (CRLs) remains elusive. Here, we report that MLN4924, a small molecule inhibitor of neddylation, causes EGR1 accumulation by inactivating SCFFBXW7 (CRL1), which is a new E3 ligase for EGR1. Specifically, FBXW7 binds to EGR1 via its consensus binding motif/degron, whereas cancer-derived FBXW7 mutants showed a much reduced EGR1 binding. SiRNA-mediated FBXW7 knockdown caused EGR1 accumulation, whereas FBXW7 overexpression reduced EGR1 levels. Likewise, FBXW7 knockdown significantly extended EGR1 protein half-life, while FBXW7 overexpression promotes polyubiquitylation of wild-type EGR1, but not EGR1-S2A mutant with the binding site abrogated. GSK3β kinase is required for the FBXW7-EGR1 binding, and for enhanced EGR1 degradation by wild type FBXW7, but not by FBXW7 mutants. Likewise, GSK3β knockdown or treatment with GSK3β inhibitor significantly increased the EGR1 levels and extended EGR1 protein half-life, while reducing EGR1 polyubiquitylation. Hypoxia exposure reduces the EGR1 levels via enhancing the FBXW7-EGR1 binding, and FBXW7-induced EGR1 polyubiquitylation. Biologically, EGR1 knockdown suppressed cancer cell growth, whereas growth stimulation by FBXW7 knockdown is partially rescued by EGR1 knockdown. Thus, EGR1 is a new substrate of the GSK3β-FBXW7 axis, and the FBXW7-EGR1 axis coordinately regulates growth of cancer cells.

Related Products

Cat.No. Product Name Information
S7109 Pevonedistat (MLN4924) MLN4924 is a small molecule inhibitor of Nedd8 activating enzyme (NAE) with IC50 of 4 nM.

Related Targets

E1 Activating