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Post-transcriptional regulation of cyclins D1, D3 and G1 and proliferation of human cancer cells depend on IMP-3 nuclear localization

Oncogene volume 33, pages 2866–2875 (2014)Cite this article

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Abstract

RNA-binding proteins of the IMP family (insulin-like growth factor 2 (IGF2) mRNA-binding proteins 1–3) are important post-transcriptional regulators of gene expression. Multiple studies have linked high expression of IMP proteins, and especially of IMP-3, to an unfavorable prognosis in numerous types of cancer. The specific importance of IMP-3 for cancer transformation remains poorly understood. We here show that all three IMPs can directly bind the mRNAs of cyclins D1, D3 and G1 (CCND1, D3 and G1) in vivo and in vitro, and yet only IMP-3 regulates the expression of these cyclins in a significant manner in six human cancer cell lines of different origins. In the absence of IMP-3, the levels of CCND1, D3 and G1 proteins fall dramatically, and the cells accumulate in the G1 phase of the cell cycle, leading to almost complete proliferation arrest. Our results show that, compared with IMP-1 and IMP-2, IMP-3 is enriched in the nucleus, where it binds the transcripts of CCND1, D3 and G1. The nuclear localization of IMP-3 depends on its protein partner HNRNPM and is indispensable for the post-transcriptional regulation of expression of the cyclins. Cytoplasmic retention of IMP-3 and HNRNPM in human cancer cells leads to significant drop in proliferation. In conclusion, a nuclear IMP-3–HNRNPM complex is important for the efficient synthesis of CCND1, D3 and G1 and for the proliferation of human cancer cells.

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References

  1. Nielsen J, Christiansen J, Lykke-Andersen J, Johnsen AH, Wewer UM, Nielsen FC . A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development. Mol Cell Biol 1999; 19: 1262–1270.

    Article  CAS  Google Scholar 

  2. Vikesaa J, Hansen TV, Jonson L, Borup R, Wewer UM, Christiansen J et al. RNA-binding IMPs promote cell adhesion and invadopodia formation. EMBO J 2006; 25: 1456–1468.

    Article  CAS  Google Scholar 

  3. Runge S, Nielsen FC, Nielsen J, Lykke-Andersen J, Wewer UM, Christiansen J . H19 RNA binds four molecules of insulin-like growth factor II mRNA-binding protein. J Biol Chem 2000; 275: 29562–29569.

    Article  CAS  Google Scholar 

  4. Chao JA, Patskovsky Y, Patel V, Levy M, Almo SC, Singer RH . ZBP1 recognition of beta-actin zipcode induces RNA looping. Genes Dev 2010; 24: 148–158.

    Article  CAS  Google Scholar 

  5. Bell JL, Wachter K, Muhleck B, Pazaitis N, Kohn M, Lederer M et al. Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs): post-transcriptional drivers of cancer progression? Cell Mol Life Sci 2012.

  6. Lochhead P, Imamura Y, Morikawa T, Kuchiba A, Yamauchi M, Liao X et al. Insulin-like growth factor 2 messenger RNA binding protein 3 (IGF2BP3) is a marker of unfavourable prognosis in colorectal cancer. Eur J Cancer 2012; 48: 3405–3413.

    Article  CAS  Google Scholar 

  7. Schaeffer DF, Owen DR, Lim HJ, Buczkowski AK, Chung SW, Scudamore CH et al. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) overexpression in pancreatic ductal adenocarcinoma correlates with poor survival. BMC Cancer 2010; 10: 59.

    Article  Google Scholar 

  8. Kobel M, Xu H, Bourne PA, Spaulding BO, Shih IeM, Mao TL et al. IGF2BP3 (IMP3) expression is a marker of unfavorable prognosis in ovarian carcinoma of clear cell subtype. Mod Pathol 2009; 22: 469–475.

    Article  Google Scholar 

  9. Boudoukha S, Cuvellier S, Polesskaya A . Role of the RNA-binding protein IMP-2 in muscle cell motility. Mol Cell Biol 2010; 30: 5710–5725.

    Article  CAS  Google Scholar 

  10. Liao B, Hu Y, Brewer G . RNA-binding protein IMP-3 promotes cell survival via IGF-II signaling after ionizing radiation. J Biol Chem 2011; 286: 31145–31152.

    Article  CAS  Google Scholar 

  11. Mongroo PS, Noubissi FK, Cuatrecasas M, Kalabis J, King CE, Johnstone CN et al. IMP-1 displays cross-talk with K-Ras and modulates colon cancer cell survival through the novel proapoptotic protein CYFIP2. Cancer Res 2011; 71: 2172–2182.

    Article  CAS  Google Scholar 

  12. Stohr N, Kohn M, Lederer M, Glass M, Reinke C, Singer RH et al. IGF2BP1 promotes cell migration by regulating MK5 and PTEN signaling. Genes Dev 2012; 26: 176–189.

    Article  Google Scholar 

  13. Gu W, Katz Z, Wu B, Park HY, Li D, Lin S et al. Regulation of local expression of cell adhesion and motility-related mRNAs in breast cancer cells by IMP1/ZBP1. J Cell Sci 2012; 125 (Pt 1): 81–91.

    Article  CAS  Google Scholar 

  14. Yisraeli JK . VICKZ proteins: a multi-talented family of regulatory RNA-binding proteins. Biol Cell 2005; 97: 87–96.

    Article  CAS  Google Scholar 

  15. Hafner M, Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P et al. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 2010; 141: 129–141.

    Article  CAS  Google Scholar 

  16. Jonson L, Vikesaa J, Krogh A, Nielsen LK, Hansen T, Borup R et al. Molecular composition of IMP1 ribonucleoprotein granules. Mol Cell Proteomics 2007; 6: 798–811.

    Article  Google Scholar 

  17. Munro TP, Kwon S, Schnapp BJ, St Johnston D . A repeated IMP-binding motif controls oskar mRNA translation and anchoring independently of Drosophila melanogaster IMP. J Cell Biol 2006; 172: 577–588.

    Article  CAS  Google Scholar 

  18. Nielsen J, Adolph SK, Rajpert-De Meyts E, Lykke-Andersen J, Koch G, Christiansen J et al. Nuclear transit of human zipcode-binding protein IMP1. Biochem J 2003; 376 (Pt 2): 383–391.

    Article  CAS  Google Scholar 

  19. Dai N, Rapley J, Angel M, Yanik MF, Blower MD, Avruch J . mTOR phosphorylates IMP2 to promote IGF2 mRNA translation by internal ribosomal entry. Genes Dev 2011; 25: 1159–1172.

    Article  CAS  Google Scholar 

  20. Hammer NA, Hansen TO, Byskov AG, Rajpert-De Meyts E, Grondahl ML, Bredkjaer HE et al. Expression of IGF-II mRNA-binding proteins (IMPs) in gonads and testicular cancer. Reproduction 2005; 130: 203–212.

    Article  CAS  Google Scholar 

  21. Liao B, Hu Y, Herrick DJ, Brewer G . The RNA-binding protein IMP-3 is a translational activator of insulin-like growth factor II leader-3 mRNA during proliferation of human K562 leukemia cells. J Biol Chem 2005; 280: 18517–18524.

    Article  CAS  Google Scholar 

  22. Sherr CJ, Roberts JM . Living with or without cyclins and cyclin-dependent kinases. Genes Dev [Review] 2004; 18: 2699–2711.

    Article  CAS  Google Scholar 

  23. Cansizoglu AE, Lee BJ, Zhang ZC, Fontoura BM, Chook YM . Structure-based design of a pathway-specific nuclear import inhibitor. Nat Struct Mol Biol 2007; 14: 452–454.

    Article  CAS  Google Scholar 

  24. Pan F, Huttelmaier S, Singer RH, Gu W . ZBP2 facilitates binding of ZBP1 to beta-actin mRNA during transcription. Mol Cell Biol 2007; 27: 8340–8351.

    Article  CAS  Google Scholar 

  25. Oleynikov Y, Singer RH . Real-time visualization of ZBP1 association with beta-actin mRNA during transcription and localization. Curr Biol 2003; 13: 199–207.

    Article  CAS  Google Scholar 

  26. Lal A, Mazan-Mamczarz K, Kawai T, Yang X, Martindale JL, Gorospe M . Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs. EMBO J 2004; 23: 3092–3102.

    Article  CAS  Google Scholar 

  27. Seo HR, Lee DH, Lee HJ, Baek M, Bae S, Soh JW et al. Cyclin G1 overcomes radiation-induced G2 arrest and increases cell death through transcriptional activation of cyclin B1. Cell Death Differ 2006; 13: 1475–1484.

    Article  CAS  Google Scholar 

  28. Fornari F, Gramantieri L, Giovannini C, Veronese A, Ferracin M, Sabbioni S et al. MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res 2009; 69: 5761–5767.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Drs Annick Harel-Bellan and Linda L Pritchard for critical reading of the manuscript, Drs Jan Christianssen and Finn C Nielsen for the kind gifts of antibodies and for helpful discussions, Dr Yuh Min Chook for the kind gift of the M9M plasmid, and Dr Antoinette Lemoine for the HCC cell lines. This work was supported by a grant from the Association Français contre les Myopathies to AP and from Fondation ARC pour la Recherche sur le Cancer to TRV.

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Authors and Affiliations

  1. CNRS, FRE 3377, Gif-sur-Yvette, France

    T Rivera Vargas, S Boudoukha, A Simon, M Souidi, G Pinna & A Polesskaya

  2. Univ Paris-Sud, FRE 3377, Gif-sur-Yvette, France

    T Rivera Vargas, S Boudoukha, A Simon, M Souidi, G Pinna & A Polesskaya

  3. CEA, FRE 3377, Gif-sur-Yvette, France

    T Rivera Vargas, S Boudoukha, A Simon, M Souidi, G Pinna & A Polesskaya

  4. Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA

    S Boudoukha

  5. Département Génétique et Développement, Inserm U1016, Institut Cochin, Paris, France

    S Cuvellier

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  1. T Rivera Vargas
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Correspondence to A Polesskaya.

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Rivera Vargas, T., Boudoukha, S., Simon, A. et al. Post-transcriptional regulation of cyclins D1, D3 and G1 and proliferation of human cancer cells depend on IMP-3 nuclear localization. Oncogene 33, 2866–2875 (2014). https://doi.org/10.1038/onc.2013.252

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