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CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer

Cepeda, Diana; Ng, Hwee-Fang; Sharifi, Hamid Reza; Mahmoudi, Salah; Soto Cerrato, Vanessa; Fredlund, Erik; Magnusson, Kristina; Nilsson, Helen; Malyukova, Alena and Rantala, Juha, et al. (2013) In EMBO Molecular Medicine 5(7). p.1067-1086
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... (More)
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. (Less)
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published
subject
keywords
Breast cancer, CDK, F-box protein, FBXO28, MYC
in
EMBO Molecular Medicine
volume
5
issue
7
pages
1067 - 1086
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • wos:000325942300009
  • scopus:84880026012
ISSN
1757-4684
DOI
10.1002/emmm.201202341
language
English
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yes
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d56615a5-4800-4e2f-9a85-c239f16afbe6 (old id 4212419)
date added to LUP
2014-01-03 10:47:55
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2019-05-28 01:12:51
@article{d56615a5-4800-4e2f-9a85-c239f16afbe6,
  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.},
  author       = {Cepeda, Diana and Ng, Hwee-Fang and Sharifi, Hamid Reza and Mahmoudi, Salah and Soto Cerrato, Vanessa and Fredlund, Erik and Magnusson, Kristina and Nilsson, Helen and Malyukova, Alena and Rantala, Juha and Klevebring, Daniel and Vinals, Francesc and Bhaskaran, Nimesh and Zakaria, Siti Mariam and Rahmanto, Aldwin Suryo and Grotegut, Stefan and Nielsen, Michael Lund and Szigyarto, Cristina Al-Khalili and Sun, Dahui and Lerner, Mikael and Navani, Sanjay and Widschwendter, Martin and Uhlen, Mathias and Jirström, Karin and Ponten, Fredrik and Wohlschlegel, James and Grander, Dan and Spruck, Charles and Larsson, Lars-Gunnar and Sangfelt, Olle},
  issn         = {1757-4684},
  keyword      = {Breast cancer,CDK,F-box protein,FBXO28,MYC},
  language     = {eng},
  number       = {7},
  pages        = {1067--1086},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {EMBO Molecular Medicine},
  title        = {CDK-mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer},
  url          = {http://dx.doi.org/10.1002/emmm.201202341},
  volume       = {5},
  year         = {2013},
}