TY - JOUR
T1 - CDK-mediated activation of the SCFFBXO28 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 - Soto Cerrato, Vanessa
AU - Fredlund, Erik
AU - Magnusson, Kristina
AU - Nilsson, Helen
AU - Malyukova, Alena
AU - Rantala, Juha
AU - Klevebring, Daniel
AU - Vinals, 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 - Uhlen, Mathias
AU - Jirström, Karin
AU - Ponten, Fredrik
AU - Wohlschlegel, James
AU - Grander, Dan
AU - Spruck, Charles
AU - Larsson, Lars-Gunnar
AU - Sangfelt, Olle
N1 - The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Pathology, (Lund) (013030000)
PY - 2013
Y1 - 2013
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.
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.
KW - Breast cancer
KW - CDK
KW - F-box protein
KW - FBXO28
KW - MYC
U2 - 10.1002/emmm.201202341
DO - 10.1002/emmm.201202341
M3 - Article
C2 - 23776131
SN - 1757-4684
VL - 5
SP - 1067
EP - 1086
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 7
ER -
