FBXO45-MYCBP2 regulates mitotic cell fate by targeting FBXW7 for degradation


Cell fate decision upon prolonged mitotic arrest induced by microtubule-targeting agents depends on the activity of the tumor suppressor and F-box protein FBXW7. FBXW7 promotes mitotic cell death and prevents premature escape from mitosis through mitotic slippage. Mitotic slippage is a process that can cause chemoresistance and tumor relapse. Therefore, understanding the mechanisms that regulate the balance between mitotic cell death and mitotic slippage is an important task. Here we report that FBXW7 protein levels markedly decline during extended mitotic arrest. FBXO45 binds to a conserved acidic N-terminal motif of FBXW7 specifically under a prolonged delay in mitosis, leading to ubiquitylation and subsequent proteasomal degradation of FBXW7 by the FBXO45-MYCBP2 E3 ubiquitin ligase. Moreover, we find that FBXO45-MYCBP2 counteracts FBXW7 in that it promotes mitotic slippage and prevents cell death in mitosis. Targeting this interaction represents a promising strategy to prevent chemotherapy resistance.

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  1. 1.

    Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67:425–79.

    CAS  PubMed  Google Scholar 

  2. 2.

    Davis RJ, Welcker M, Clurman BE. Tumor suppression by the Fbw7 ubiquitin ligase: mechanisms and opportunities. Cancer Cell. 2014;26:455–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Nateri AS, Riera-Sans L, Da Costa C, Behrens A. The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling. Science. 2004;303:1374–8.

    CAS  PubMed  Google Scholar 

  4. 4.

    Wei W, Jin J, Schlisio S, Harper JW, Kaelin WG Jr. The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell. 2005;8:25–33.

    CAS  PubMed  Google Scholar 

  5. 5.

    Welcker M, Orian A, Jin J, Grim JE, Harper JW, Eisenman RN, et al. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci USA. 2004;101:9085–90.

    CAS  Google Scholar 

  6. 6.

    Yada M, Hatakeyama S, Kamura T, Nishiyama M, Tsunematsu R, Imaki H, et al. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J. 2004;23:2116–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Koepp DM, Schaefer LK, Ye X, Keyomarsi K, Chu C, Harper JW, et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science. 2001;294:173–7.

    CAS  PubMed  Google Scholar 

  8. 8.

    Moberg KH, Bell DW, Wahrer DC, Haber DA, Hariharan IK. Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature. 2001;413:311–6.

    CAS  PubMed  Google Scholar 

  9. 9.

    Strohmaier H, Spruck CH, Kaiser P, Won KA, Sangfelt O, Reed SI. Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature. 2001;413:316–22.

    CAS  PubMed  Google Scholar 

  10. 10.

    Hubbard EJ, Wu G, Kitajewski J, Greenwald I. sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins. Genes Dev. 1997;11:3182–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Gupta-Rossi N, Le Bail O, Gonen H, Brou C, Logeat F, Six E, et al. Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor. J Biol Chem. 2001;276:34371–8.

    CAS  PubMed  Google Scholar 

  12. 12.

    Galan JM, Peter M. Ubiquitin-dependent degradation of multiple F-box proteins by an autocatalytic mechanism. Proc Natl Acad Sci USA. 1999;96:9124–9.

    CAS  PubMed  Google Scholar 

  13. 13.

    Duda DM, Olszewski JL, Tron AE, Hammel M, Lambert LJ, Waddell MB, et al. Structure of a glomulin-RBX1-CUL1 complex: inhibition of a RING E3 ligase through masking of its E2-binding surface. Mol Cell. 2012;47:371–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Tron AE, Arai T, Duda DM, Kuwabara H, Olszewski JL, Fujiwara Y, et al. The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7. Mol Cell. 2012;46:67–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Ekholm-Reed S, Goldberg MS, Schlossmacher MG, Reed SI. Parkin-dependent degradation of the F-box protein Fbw7beta promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1. Mol Cell Biol. 2013;33:3627–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Cizmecioglu O, Krause A, Bahtz R, Ehret L, Malek N, Hoffmann I. Plk2 regulates centriole duplication through phosphorylation-mediated degradation of Fbxw7 (human Cdc4). J Cell Sci. 2012;125(Pt 4):981–92.

    CAS  PubMed  Google Scholar 

  17. 17.

    Rieder CL, Maiato H. Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. Dev Cell. 2004;7:637–51.

    CAS  PubMed  Google Scholar 

  18. 18.

    Brito DA, Rieder CL. Mitotic checkpoint slippage in humans occurs via cyclin B destruction in the presence of an active checkpoint. Curr Biol. 2006;16:1194–1200.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Frederiks CN, Lam SW, Guchelaar HJ, Boven E. Genetic polymorphisms and paclitaxel- or docetaxel-induced toxicities: a systematic review. Cancer Treat Rev. 2015;41:935–50.

    CAS  PubMed  Google Scholar 

  20. 20.

    Haschka M, Karbon G, Fava LL, Villunger A. Perturbing mitosis for anti-cancer therapy: is cell death the only answer? EMBO Rep. 2018;19:e45440.

  21. 21.

    Finkin S, Aylon Y, Anzi S, Oren M, Shaulian E. Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy. Oncogene. 2008;27:4411–21.

    CAS  PubMed  Google Scholar 

  22. 22.

    Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ, et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature. 2011;471:110–4.

    CAS  PubMed  Google Scholar 

  23. 23.

    Grill B, Murphey RK, Borgen MA. The PHR proteins: intracellular signaling hubs in neuronal development and axon degeneration. Neural Dev. 2016;11:8.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Po MD, Hwang C, Zhen M. PHRs: bridging axon guidance, outgrowth and synapse development. Curr Opin Neurobiol. 2010;20:100–7.

    CAS  PubMed  Google Scholar 

  25. 25.

    Chen X, Sahasrabuddhe AA, Szankasi P, Chung F, Basrur V, Rangnekar VM, et al. Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival. Cell Death Differ. 2014;21:1535–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Kugler JM, Woo JS, Oh BH, Lasko P. Regulation of Drosophila vasa in vivo through paralogous cullin-RING E3 ligase specificity receptors. Mol Cell Biol. 2010;30:1769–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Nakata K, Abrams B, Grill B, Goncharov A, Huang X, Chisholm AD, et al. Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development. Cell. 2005;120:407–20.

    CAS  PubMed  Google Scholar 

  28. 28.

    Xiong X, Hao Y, Sun K, Li J, Li X, Mishra B, et al. The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein. PLoS Biol. 2012;10:e1001440.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Allan LA, Skowyra A, Rogers KI, Zeller D, Clarke PR. Atypical APC/C-dependent degradation of Mcl-1 provides an apoptotic timer during mitotic arrest. EMBO J. 2018;37:e96831.

  30. 30.

    Harley ME, Allan LA, Sanderson HS, Clarke PR. Phosphorylation of Mcl-1 by CDK1-cyclin B1 initiates its Cdc20-dependent destruction during mitotic arrest. EMBO J. 2010;29:2407–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Kourtis N, Moubarak RS, Aranda-Orgilles B, Lui K, Aydin IT, Trimarchi T, et al. FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification. Nat Cell Biol. 2015;17:322–32.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Huttlin EL, Bruckner RJ, Paulo JA, Cannon JR, Ting L, Baltier K, et al. Architecture of the human interactome defines protein communities and disease networks. Nature. 2017;545:505–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Liao EH, Hung W, Abrams B, Zhen M. An SCF-like ubiquitin ligase complex that controls presynaptic differentiation. Nature. 2004;430:345–50.

    CAS  PubMed  Google Scholar 

  34. 34.

    Welcker M, Clurman BE. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer. 2008;8:83–93.

    CAS  PubMed  Google Scholar 

  35. 35.

    Skaar JR, Pagan JK, Pagano M. Mechanisms and function of substrate recruitment by F-box proteins. Nat Rev Mol Cell Biol. 2013;14:369–81.

    CAS  PubMed  Google Scholar 

  36. 36.

    Kimura T, Gotoh M, Nakamura Y, Arakawa H. hCDC4b, a regulator of cyclin E, as a direct transcriptional target of p53. Cancer Sci. 2003;94:431–6.

    CAS  PubMed  Google Scholar 

  37. 37.

    Pierre SC, Hausler J, Birod K, Geisslinger G, Scholich K. PAM mediates sustained inhibition of cAMP signaling by sphingosine-1-phosphate. EMBO J. 2004;23:3031–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Brito DA, Yang Z, Rieder CL. Microtubules do not promote mitotic slippage when the spindle assembly checkpoint cannot be satisfied. J Cell Biol. 2008;182:623–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Gascoigne KE, Taylor SS. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell. 2008;14:111–22.

    CAS  PubMed  Google Scholar 

  40. 40.

    Sloss O, Topham C, Diez M, Taylor S. Mcl-1 dynamics influence mitotic slippage and death in mitosis. Oncotarget. 2016;7:5176–92.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

    Google Scholar 

  42. 42.

    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Pao KC, Wood NT, Knebel A, Rafie K, Stanley M, Mabbitt PD, et al. Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity. Nature. 2018;556:381–5.

    CAS  PubMed  Google Scholar 

  44. 44.

    Reiterer V, Figueras-Puig C, Le Guerroue F, Confalonieri S, Vecchi M, Jalapothu D, et al. The pseudophosphatase STYX targets the F-box of FBXW7 and inhibits SCFFBXW7 function. EMBO J. 2017;36:260–73.

    CAS  PubMed  Google Scholar 

  45. 45.

    He D, Ma Z, Fang C, Ding J, Yang W, Chen P, et al. Pseudophosphatase STYX promotes tumor growth and metastasis by inhibiting FBXW7 function in colorectal cancer. Cancer Lett. 2019;454:53–65.

    CAS  PubMed  Google Scholar 

  46. 46.

    Gorelik M, Orlicky S, Sartori MA, Tang X, Marcon E, Kurinov I, et al. Inhibition of SCF ubiquitin ligases by engineered ubiquitin variants that target the Cul1 binding site on the Skp1-F-box interface. Proc Natl Acad Sci USA. 2016;113:3527–32.

    CAS  PubMed  Google Scholar 

  47. 47.

    Kratz AS, Richter KT, Schlosser YT, Schmitt M, Shumilov A, Delecluse HJ, et al. Fbxo28 promotes mitotic progression and regulates topoisomerase IIalpha-dependent DNA decatenation. Cell Cycle. 2016;15:3419–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Dorr A, Pierre S, Zhang DD, Henke M, Holland S, Scholich K. MYCBP2 is a guanosine exchange factor for ran protein and determines its localization in neurons of dorsal root ganglia. J Biol Chem. 2015;290:25620–35.

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Hoffmann I, Draetta G, Karsenti E. Activation of the phosphatase activity of human cdc25A by a cdk2-cyclin E dependent phosphorylation at the G1/S transition. EMBO J. 1994;13:4302–10.

    CAS  PubMed  PubMed Central  Google Scholar 

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We thank B.E. Clurman, D. Gerlich, L. Hengst, F. Melchior, G. Melino, J.D. Parvin, A. Peschiaroli, and K. Scholich for providing reagents and cell lines. We acknowledge the DKFZ Mass Spectrometry and Microscopy Core Facilities for providing equipment and excellent technical assistance. We thank Bettina Dörr for expert technical assistance. We acknowledge the members of our lab for critically reading the manuscript.

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IH and KTR designed the experiments. KTR, YTK, and BV performed the experiments. IH and KTR wrote the paper.

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Correspondence to Ingrid Hoffmann.

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Richter, K.T., Kschonsak, Y.T., Vodicska, B. et al. FBXO45-MYCBP2 regulates mitotic cell fate by targeting FBXW7 for degradation. Cell Death Differ 27, 758–772 (2020). https://doi.org/10.1038/s41418-019-0385-7

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