CDK-mediated Activation of the SCF(FBXO) (28) Ubiquitin Ligase Promotes MYC-driven Transcription and Tumourigenesis and Predicts Poor Survival in Breast Cancer

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2013 Jun 19

PMID 23776131

Citations 46

Authors

Diana Cepeda

Hwee-Fang Ng

Hamid Reza Sharifi

Salah Mahmoudi

Vanessa Soto Cerrato

Erik Fredlund

Kristina Magnusson

Helen Nilsson

Alena Malyukova

Juha Rantala

Daniel Klevebring

Francesc Vinals

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 Uhlen

Karin Jirstrom

Fredrik Ponten

James Wohlschlegel

Dan Grander

Charles Spruck

Lars-Gunnar Larsson

Olle Sangfelt

Affiliations

Soon will be listed here.

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.

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References

Bouchard C, Marquardt J, Bras A, Medema R, Eilers M . Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins. EMBO J. 2004; 23(14):2830-40. PMC: 514943. DOI: 10.1038/sj.emboj.7600279. View

Meyer N, Penn L . Reflecting on 25 years with MYC. Nat Rev Cancer. 2008; 8(12):976-90. DOI: 10.1038/nrc2231. View

Rahl P, Lin C, Seila A, Flynn R, McCuine S, Burge C . c-Myc regulates transcriptional pause release. Cell. 2010; 141(3):432-45. PMC: 2864022. DOI: 10.1016/j.cell.2010.03.030. View

Eberhardy S, Farnham P . c-Myc mediates activation of the cad promoter via a post-RNA polymerase II recruitment mechanism. J Biol Chem. 2001; 276(51):48562-71. DOI: 10.1074/jbc.M109014200. View

Pickart C . Back to the future with ubiquitin. Cell. 2004; 116(2):181-90. DOI: 10.1016/s0092-8674(03)01074-2. View

Sjostrom S, Finn G, Hahn W, Rowitch D, Kenney A . The Cdk1 complex plays a prime role in regulating N-myc phosphorylation and turnover in neural precursors. Dev Cell. 2005; 9(3):327-38. DOI: 10.1016/j.devcel.2005.07.014. View

Fredlund E, Ringner M, Maris J, Pahlman S . High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Proc Natl Acad Sci U S A. 2008; 105(37):14094-9. PMC: 2544584. DOI: 10.1073/pnas.0804455105. View

Carrano A, Eytan E, Hershko A, Pagano M . SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol. 1999; 1(4):193-9. DOI: 10.1038/12013. View

Hydbring P, Bahram F, Su Y, Tronnersjo S, Hogstrand K, von der Lehr N . Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation. Proc Natl Acad Sci U S A. 2009; 107(1):58-63. PMC: 2806698. DOI: 10.1073/pnas.0900121106. View

10.

Choi S, Wright J, Gerber S, Cole M . Myc protein is stabilized by suppression of a novel E3 ligase complex in cancer cells. Genes Dev. 2010; 24(12):1236-41. PMC: 2885659. DOI: 10.1101/gad.1920310. View

11.

Guccione E, Martinato F, Finocchiaro G, Luzi L, Tizzoni L, Dall Olio V . Myc-binding-site recognition in the human genome is determined by chromatin context. Nat Cell Biol. 2006; 8(7):764-70. DOI: 10.1038/ncb1434. View

12.

Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W . c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell. 2012; 151(1):68-79. PMC: 3471363. DOI: 10.1016/j.cell.2012.08.033. View

13.

Chen Z, Sun L . Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell. 2009; 33(3):275-86. DOI: 10.1016/j.molcel.2009.01.014. View

14.

Soderberg O, Gullberg M, Jarvius M, Ridderstrale K, Leuchowius K, Jarvius J . Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods. 2006; 3(12):995-1000. DOI: 10.1038/nmeth947. View

15.

Bashir T, Pagano M . Aberrant ubiquitin-mediated proteolysis of cell cycle regulatory proteins and oncogenesis. Adv Cancer Res. 2003; 88:101-44. DOI: 10.1016/s0065-230x(03)88305-7. View

16.

Nakayama K, Nakayama K . Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer. 2006; 6(5):369-81. DOI: 10.1038/nrc1881. View

17.

Zhao X, Heng J, Guardavaccaro D, Jiang R, Pagano M, Guillemot F . The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nat Cell Biol. 2008; 10(6):643-53. PMC: 2680438. DOI: 10.1038/ncb1727. View

18.

Vervoorts J, Luscher-Firzlaff J, Rottmann S, Lilischkis R, Walsemann G, Dohmann K . Stimulation of c-MYC transcriptional activity and acetylation by recruitment of the cofactor CBP. EMBO Rep. 2003; 4(5):484-90. PMC: 1319176. DOI: 10.1038/sj.embor.embor821. View

19.

Larsson L, Henriksson M . The Yin and Yang functions of the Myc oncoprotein in cancer development and as targets for therapy. Exp Cell Res. 2010; 316(8):1429-37. DOI: 10.1016/j.yexcr.2010.03.025. View

20.

Strohmaier H, Spruck C, Kaiser P, Won K, Sangfelt O, Reed S . Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature. 2001; 413(6853):316-22. DOI: 10.1038/35095076. View