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

被引：66

作者：

Cepeda, Diana ^{[1
,2
]}

Ng, Hwee-Fang ^{[1
]}

Sharifi, Hamid Reza ^{[3
]}

Mahmoudi, Salah ^{[1
]}

Soto Cerrato, Vanessa ^{[4
]}

Fredlund, Erik ^{[3
]}

Magnusson, Kristina ^{[5
]}

Nilsson, Helen ^{[3
]}

Malyukova, Alena ^{[1
,2
]}

Rantala, Juha ^{[6
]}

Klevebring, Daniel ^{[7
]}

Vinals, Francesc ^{[8
,9
]}

Bhaskaran, Nimesh ^{[1
]}

Zakaria, Siti Mariam ^{[3
]}

Rahmanto, Aldwin Suryo ^{[1
]}

Grotegut, Stefan ^{[10
]}

Nielsen, Michael Lund ^{[11
]}

Szigyarto, Cristina Al-Khalili ^{[12
]}

Sun, Dahui ^{[10
]}

Lerner, Mikael ^{[2
]}

Navani, Sanjay ^{[5
]}

Widschwendter, Martin ^{[13
]}

Uhlen, Mathias ^{[12
]}

Jirstrom, Karin ^{[14
]}

Ponten, Fredrik ^{[5
]}

Wohlschlegel, James ^{[15
]}

Grander, Dan ^{[2
]}

Spruck, Charles ^{[10
]}

Larsson, Lars-Gunnar ^{[3
]}

Sangfelt, Olle ^{[1
,2
]}

机构：

[1] Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden

[2] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden

[3] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden

[4] Univ Barcelona, Fac Med, Dept Pathol & Expt Therapeut, Canc Cell Biol Res Grp, Barcelona 7, Spain

[5] Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden

[6] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA

[7] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[8] IDIBELL, Catalan Inst Oncol, Translat Res Lab, Lhospitalet De Llobregat, Spain

[9] Univ Barcelona, Physiol Sci Dept 2, Barcelona, Spain

[10] Sanford Burnham Med Res Inst, La Jolla, CA USA

[11] Fac Hlth Sci, NNF Ctr Prot Res, Copenhagen, Denmark

[12] KTH Alba Nova Univ Ctr, Dept Biotechnol, Stockholm, Sweden

[13] UCL, Dept Womens Canc, UCL Elizabeth Garrett Anderson Inst Womens Hlth, London WC1E 6BT, England

[14] Lund Univ, Dept Lab Med, Ctr Mol Pathol, Skane Univ Hosp, Lund, Sweden

[15] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA

来源：

EMBO MOLECULAR MEDICINE | 2013年 / 5卷 / 07期

基金：

瑞典研究理事会; 美国国家卫生研究院;

关键词：

Breast cancer; CDK; F-box protein; FBXO28; MYC; F-BOX PROTEINS; C-MYC; CELL-CYCLE; BETA-TRCP; TUMOR-SUPPRESSOR; PHOSPHORYLATION; DEGRADATION; SKP2; PROTEOLYSIS; PROLIFERATION;

D O I：

10.1002/emmm.201202341

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：1067 / 1086

页数：20

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