CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer

Diana Cepeda; Hwee-Fang Ng; Hamid Reza Sharifi; Salah Mahmoudi; Vanessa Soto Cerrato; Erik Fredlund; Kristina Magnusson; Helén Nilsson; Alena Malyukova; Juha Rantala; Daniel Klevebring; Francesc Viñals; Nimesh Bhaskaran; Siti Mariam Zakaria; Aldwin Suryo Rahmanto; Stefan Grotegut; Michael Lund Nielsen; Cristina Al-Khalili Szigyarto; Dahui Sun; Mikael Lerner; Sanjay Navani; Martin Widschwendter; Mathias Uhlén; Karin Jirström; Fredrik Pontén; James Wohlschlegel; Dan Grandér; Charles Spruck; Lars-Gunnar Larsson; Olle Sangfelt

doi:10.1002/emmm.201202341

CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer

Diana Cepeda, Hwee-Fang Ng, Hamid Reza Sharifi, Salah Mahmoudi, Vanessa Soto Cerrato, Erik Fredlund, Kristina Magnusson, Helén Nilsson, Alena Malyukova, Juha Rantala, Daniel Klevebring, Francesc Viñals, Nimesh Bhaskaran, Siti Mariam Zakaria, Aldwin Suryo Rahmanto, Stefan Grotegut, Michael Lund Nielsen, Cristina Al-Khalili Szigyarto, Dahui Sun, Mikael LernerSanjay Navani, Martin Widschwendter, Mathias Uhlén, Karin Jirström, Fredrik Pontén, James Wohlschlegel, Dan Grandér, Charles Spruck, Lars-Gunnar Larsson, Olle Sangfelt

Novo Nordisk Foundation Center for Protein Research

46 Citations (Scopus)

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. SCF^FBXO28 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 SCF^FBXO28 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.

Original language	English
Journal	E M B O Molecular Medicine (Online)
Volume	5
Issue number	7
Pages (from-to)	1067-1086
Number of pages	20
ISSN	1757-4676
DOIs	https://doi.org/10.1002/emmm.201202341
Publication status	Published - 3 Jul 2013

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Cepeda, D., Ng, H-F., Sharifi, H. R., Mahmoudi, S., Cerrato, V. S., Fredlund, E., Magnusson, K., Nilsson, H., Malyukova, A., Rantala, J., Klevebring, D., Viñals, F., Bhaskaran, N., Zakaria, S. M., Rahmanto, A. S., Grotegut, S., Nielsen, M. L., Szigyarto, C. A-K., Sun, D., ... Sangfelt, O. (2013). CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer. E M B O Molecular Medicine (Online), 5(7), 1067-1086. https://doi.org/10.1002/emmm.201202341

CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer. / Cepeda, Diana; Ng, Hwee-Fang; Sharifi, Hamid Reza et al.

In: E M B O Molecular Medicine (Online), Vol. 5, No. 7, 03.07.2013, p. 1067-1086.

Research output: Contribution to journal › Journal article › Research › peer-review

Cepeda, D, Ng, H-F, Sharifi, HR, Mahmoudi, S, Cerrato, VS, Fredlund, E, Magnusson, K, Nilsson, H, Malyukova, A, Rantala, J, Klevebring, D, Viñals, F, Bhaskaran, N, Zakaria, SM, Rahmanto, AS, Grotegut, S, Nielsen, ML, Szigyarto, CA-K, Sun, D, Lerner, M, Navani, S, Widschwendter, M, Uhlén, M, Jirström, K, Pontén, F, Wohlschlegel, J, Grandér, D, Spruck, C, Larsson, L-G & Sangfelt, O 2013, 'CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer', E M B O Molecular Medicine (Online), vol. 5, no. 7, pp. 1067-1086. https://doi.org/10.1002/emmm.201202341

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title = "CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer",

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. 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.",

author = "Diana Cepeda and Hwee-Fang Ng and Sharifi, {Hamid Reza} and Salah Mahmoudi and Cerrato, {Vanessa Soto} and Erik Fredlund and Kristina Magnusson and Hel{\'e}n Nilsson and Alena Malyukova and Juha Rantala and Daniel Klevebring and Francesc Vi{\~n}als and Nimesh Bhaskaran and Zakaria, {Siti Mariam} and Rahmanto, {Aldwin Suryo} and Stefan Grotegut and Nielsen, {Michael Lund} and Szigyarto, {Cristina Al-Khalili} and Dahui Sun and Mikael Lerner and Sanjay Navani and Martin Widschwendter and Mathias Uhl{\'e}n and Karin Jirstr{\"o}m and Fredrik Pont{\'e}n and James Wohlschlegel and Dan Grand{\'e}r and Charles Spruck and Lars-Gunnar Larsson and Olle Sangfelt",

note = "{\textcopyright} 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.",

year = "2013",

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doi = "10.1002/emmm.201202341",

language = "English",

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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

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 -

CDK-mediated activation of the SCF(FBXO) (28) ubiquitin ligase promotes MYC-driven transcription and tumourigenesis and predicts poor survival in breast cancer

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