CDK‐mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC‐driven transcription and tumourigenesis and predicts poor survival in breast cancer
Open Access
- 14 June 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in EMBO Molecular Medicine
- Vol. 5 (7), 1067-1086
- https://doi.org/10.1002/emmm.201202341
Abstract
SCF (Skp1/Cul1/F‐box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F‐box protein, FBXO28 that controls MYC‐dependent transcription by non‐proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2‐mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F‐box mutant unable to support MYC ubiquitylation results in an impairment of MYC‐driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK‐FBXO28‐MYC axis as a potential molecular drug target in MYC‐driven cancers, including breast cancer.Keywords
This publication has 52 references indexed in Scilit:
- c-Myc Regulates Transcriptional Pause ReleaseCell, 2010
- Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformationProceedings of the National Academy of Sciences of the United States of America, 2009
- Myc’s broad reachGenes & Development, 2008
- High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastomaProceedings of the National Academy of Sciences of the United States of America, 2008
- Mitotic CDKs control the metaphase–anaphase transition and trigger spindle elongationGenes & Development, 2008
- Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancerNature Reviews Cancer, 2008
- The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoproteinNature, 2008
- Phosphorylation of Skp2 regulated by CDK2 and Cdc14B protects it from degradation by APCCdh1 in G1 phaseThe EMBO Journal, 2008
- Direct observation of individual endogenous protein complexes in situ by proximity ligationNature Methods, 2006
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005