TY - JOUR
T1 - CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer
AU - Cepeda, Diana
AU - Ng, Hwee-Fang
AU - Sharifi, Hamid Reza
AU - Mahmoudi, Salah
AU - Cerrato, Vanessa Soto
AU - Fredlund, Erik
AU - Magnusson, Kristina
AU - Nilsson, Helén
AU - Malyukova, Alena
AU - Rantala, Juha
AU - Klevebring, Daniel
AU - Viñals, Francesc
AU - Bhaskaran, Nimesh
AU - Zakaria, Siti Mariam
AU - Rahmanto, Aldwin Suryo
AU - Grotegut, Stefan
AU - Nielsen, Michael Lund
AU - Szigyarto, Cristina Al-Khalili
AU - Sun, Dahui
AU - Lerner, Mikael
AU - Navani, Sanjay
AU - Widschwendter, Martin
AU - Uhlén, Mathias
AU - Jirström, Karin
AU - Pontén, Fredrik
AU - Wohlschlegel, James
AU - Grandér, Dan
AU - Spruck, Charles
AU - Larsson, Lars-Gunnar
AU - Sangfelt, Olle
N1 - © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.
PY - 2013/7/3
Y1 - 2013/7/3
N2 - 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. FBXO28 is identified as part of a SCF complex acting as a regulator of tumor cell proliferation and an important modifier of MYC function. FBXO28 may be a new prognostic factor in breast cancer and a new potential drug target in MYC- driven tumors.
AB - 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. FBXO28 is identified as part of a SCF complex acting as a regulator of tumor cell proliferation and an important modifier of MYC function. FBXO28 may be a new prognostic factor in breast cancer and a new potential drug target in MYC- driven tumors.
U2 - 10.1002/emmm.201202341
DO - 10.1002/emmm.201202341
M3 - Journal article
C2 - 23776131
SN - 1757-4676
VL - 5
SP - 1067
EP - 1086
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 7
ER -
