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G3BP1 and G3BP2 regulate translation of interferon-stimulated genes: IFITM1, IFITM2 and IFITM3 in the cancer cell line MCF7

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G3BPs are members of an RNA-binding protein family and their aberrant expression is common in various cancers and there is growing evidence that G3BPs possess antiviral activities and are targeted by various viruses. G3BPs have also been implicated in both stabilization and degradation of specific mRNAs as well as translational control of mRNA targets. G3BPs have been shown to control translation of interferon-stimulated genes (ISGs), implying that G3BPs are involved in the regulation of the interferon system in response to viral infections and/or cellular stress. The interferon induced transmembrane (IFITM1, IFITM2 and IFITM3) proteins are antiviral proteins, and are also involved in cancer progression and metastasis. Therefore, these genes were selected in the studies reported here as potential transcript targets of G3BPs. Furthermore, G3BPs are involved in the regulation of the MEK pathway which also impacts on the translation of ISGs. Therefore, the role of this pathway was also analysed in regulation of IFITM1-3 proteins. Overall, this research study suggests that G3BPs are essential for the accumulation of IFITM1-3 proteins and intersect twice in the regulation of IFITM1-3 expression, first through MEK pathway and then through an interaction with the 3′-UTRs of its target transcripts. However, it is still to be determined whether the two apparent functions are part of a single control mechanism or the two functions are mutually exclusive.

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References

  1. Halbeisen RE, Galgano A, Scherrer T, Gerber AP (2008) Post-transcriptional gene regulation: from genome-wide studies to principles. Cell Mol Life Sci 65:798–813

    Article  CAS  PubMed  Google Scholar 

  2. Kennedy D, French J, Guitard E, Ru K, Tocque B, Mattick J (2001) Characterization of G3BPs: tissue specific expression, chromosomal localisation and rasGAP(120) binding studies. J Cell Biochem 84:173–187

    Article  CAS  PubMed  Google Scholar 

  3. Parker F, Maurier F, Delumeau I, Duchesne M, Faucher D, Debussche L, Dugue A, Schweighoffer F, Tocque B (1996) A Ras-GTPase-activating protein SH3-domain-binding protein. Mol Cell Biol 16:2561–2569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gallouzi I-E, Parker F, Chebli K, Maurier F, Labourier E, Barlat I, Capony J-P, Tocque B, Tazi J (1998) A novel phosphorylation-dependent RNase activity of GAP-SH3 binding protein: a potential link between signal transduction and RNA stability. Mol Cell Biol 18:3956–3965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Taniuchi K, Nishimori I, Hollingsworth MA (2011) The N-terminal domain of G3BP enhances cell motility and invasion by posttranscriptional regulation of BART. Mol Cancer Res 9:856–866

    Article  CAS  PubMed  Google Scholar 

  6. Bikkavilli RK, Malbon CC (2011) Arginine methylation of G3BP1 in response to Wnt3a regulates β-catenin mRNA. J Cell Sci 124:2310–2320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zekri L, Chebli K, Tourriere H, Nielsen FC, Hansen TV, Rami A, Tazi J (2005) Control of fetal growth and neonatal survival by the RasGAP-associated endoribonuclease G3BP. Mol Cell Biol 25:8703–8719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Atlas R, Behar L, Elliott E, Ginzburg I (2004) The insulin-like growth factor mRNA binding-protein IMP-1 and the Ras-regulatory protein G3BP associate with tau mRNA and HuD protein in differentiated P19 neuronal cells. J Neurochem 89:613–626

    Article  CAS  PubMed  Google Scholar 

  9. Lypowy J, Chen I-Y, Abdellatif M (2005) An Alliance between Ras GTPase-activating protein, filamin C, and Ras GTPase-activating protein SH3 domain-binding protein regulates myocyte growth. J Biol Chem 280:25717–25728

    Article  CAS  PubMed  Google Scholar 

  10. Ortega ÁD, Willers IM, Sala S, Cuezva JM (2010) Human G3BP1 interacts with β-F1-ATPase mRNA and inhibits its translation. J Cell Sci 123:2685–2696

    Article  CAS  PubMed  Google Scholar 

  11. Gupta N, Badeaux M, Liu Y, Naxerova K, Sgroi D, Munn LL, Jain RK, Garkavtsev I (2017) Stress granule-associated protein G3BP2 regulates breast tumor initiation. Proc Natl Acad Sci 114:1033–1038

    Article  CAS  PubMed  Google Scholar 

  12. Gajewski TF, Corrales L (2015) New perspectives on type I IFNs in cancer. Cytokine Growth Factor Rev 26:175–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Catharina Hagerling A-JC, Werb Zena (2015) Balancing the innate immune system in tumor development. Trends Cell Biol 25:214–220

    Article  CAS  PubMed  Google Scholar 

  14. Choi HJ, Lui A, Ogony J, Jan R, Sims PJ, Lewis-Wambi J (2015) Targeting interferon response genes sensitizes aromatase inhibitor resistant breast cancer cells to estrogen-induced cell death. Breast Cancer Res 17:6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. van Boxel-Dezaire AHH, Rani MRS, Stark GR (2006) Complex modulation of cell type-specific signaling in response to type I interferons. Immunity 25:361–372

    Article  CAS  PubMed  Google Scholar 

  16. Iwasaki A, Medzhitov R (2015) Control of adaptive immunity by the innate immune system. Nat Immunol 16:343–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Galan A, Lozano G, Piñeiro D, Martinez-Salas E (2017) G3BP1 interacts directly with the FMDV IRES and negatively regulates translation. FEBS J 284:3202–3217

    Article  CAS  PubMed  Google Scholar 

  18. Scholte FEM, Tas A, Albulescu IC, Žusinaite E, Merits A, Snijder EJ, van Hemert MJ (2015) Stress granule components G3BP1 and G3BP2 play a proviral role early in chikungunya virus replication. J Virol 89:4457–4469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cristea IM, Carroll J-WN, Rout MP, Rice CM, Chait BT, MacDonald MR (2006) Tracking and elucidating alphavirus-host protein interactions. J Biol Chem 281:30269–30278

    Article  CAS  PubMed  Google Scholar 

  20. White JP, Cardenas AM, Marissen WE, Lloyd RE (2007) Inhibition of cytoplasmic mRNA stress granule formation by a viral proteinase. Cell Host Microbe 2:295–305

    Article  CAS  PubMed  Google Scholar 

  21. Panas MD, Varjak M, Lulla A, Er Eng K, Merits A, Karlsson Hedestam GB, McInerney GM (2012) Sequestration of G3BP coupled with efficient translation inhibits stress granules in Semliki Forest virus infection. Mol Biol Cell 23:4701–4712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bidet K, Dadlani D, Garcia-Blanco MA (2014) G3BP1, G3BP2 and CAPRIN1 are required for translation of interferon stimulated mRNAs and are targeted by a dengue virus non-coding RNA. PLoS Pathog 10:e1004242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Borden EC, Sen GC, Uze G, Silverman RH, Ransohoff RM, Foster GR, Stark GR (2007) Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov 6:975–990

    Article  CAS  PubMed  Google Scholar 

  24. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565

    Article  CAS  PubMed  Google Scholar 

  25. Khodarev NN, Roizman B, Weichselbaum RR (2012) Molecular pathways: interferon/Stat1 pathway: role in the tumor resistance to genotoxic stress and aggressive growth. Clin Cancer Res 18:3015

    Article  CAS  PubMed  Google Scholar 

  26. Lee H-J, Zhuang G, Cao Y, Du P, Kim H-J, Settleman J (2014) Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell 26:207–221

    Article  CAS  PubMed  Google Scholar 

  27. Khodarev NN, Beckett M, Labay E, Darga T, Roizman B, Weichselbaum RR (2004) STAT1 is overexpressed in tumors selected for radioresistance and confers protection from radiation in transduced sensitive cells. Proc Natl Acad Sci USA 101:1714–1719

    Article  CAS  PubMed  Google Scholar 

  28. Hickford D, Frankenberg S, Shaw G, Renfree MB (2012) Evolution of vertebrate interferon inducible transmembrane proteins. BMC Genom 13:155

    Article  CAS  Google Scholar 

  29. Diamond MS, Farzan M (2013) The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat Rev Immunol 13:46–57

    Article  CAS  PubMed  Google Scholar 

  30. Yu F, Ng SSM, Chow BKC, Sze J, Lu G, Poon WS, Kung H-F, Lin MCM (2011) Knockdown of interferon-induced transmembrane protein 1 (IFITM1) inhibits proliferation, migration, and invasion of glioma cells. J Neurooncol 103:187–195

    Article  CAS  PubMed  Google Scholar 

  31. Lau SL-Y, Yuen M-L, Kou CY-C, Au K-W, Zhou J, Tsui SK-W (2012) Interferons induce the expression of IFITM1 and IFITM3 and suppress the proliferation of rat neonatal cardiomyocytes. J Cell Biochem 113:841–847

    Article  CAS  PubMed  Google Scholar 

  32. Daniel-Carmi V, Makovitzki-Avraham E, Reuven E-M, Goldstein I, Zilkha N, Rotter V, Tzehoval E, Eisenbach L (2009) The human 1-8D gene (IFITM2) is a novel p53 independent pro-apoptotic gene. Int J Cancer 125:2810–2819

    Article  CAS  PubMed  Google Scholar 

  33. Yu F, Xie D, Ng SS, Lum CT, Cai M-Y, Cheung WK, Kung H-F, Lin G, Wang X, Lin MC (2015) IFITM1 promotes the metastasis of human colorectal cancer via CAV-1. Cancer Lett 368:135–143

    Article  CAS  PubMed  Google Scholar 

  34. Ogony J, Choi HJ, Lui A, Cristofanilli M, Lewis-Wambi J (2016) Interferon-induced transmembrane protein 1 (IFITM1) overexpression enhances the aggressive phenotype of SUM149 inflammatory breast cancer cells in a signal transducer and activator of transcription 2 (STAT2)-dependent manner. Breast Cancer Res 18:25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yang M, Gao H, Chen P, Jia J, Wu S (2013) Knockdown of interferon-induced transmembrane protein 3 expression suppresses breast cancer cell growth and colony formation and affects the cell cycle. Oncol Rep 30:171–178

    Article  CAS  PubMed  Google Scholar 

  36. Zhang H, Zhang S, He H, Zhang C, Yu D, Shao R (2013) Downregulation of G3BPs inhibits the growth, migration and invasion of human lung carcinoma H1299 cells by suppressing the Src/FAK-associated signaling pathway. Cancer Gene Ther 20:622–629

    Article  CAS  PubMed  Google Scholar 

  37. Joshi S, Kaur S, Kroczynska B, Platanias LC (2010) Mechanisms of mRNA translation of interferon stimulated genes. Cytokine 52:123–127

    Article  CAS  PubMed  Google Scholar 

  38. Borden KLB (2016) The eukaryotic translation initiation factor eIF4E wears a “cap” for many occasions. Translation 4:e1220899

    Article  PubMed  PubMed Central  Google Scholar 

  39. Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KLB (2006) eIF4E is a central node of an RNA regulon that governs cellular proliferation. J Cell Biol 175:415–426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Topisirovic I, Ruiz-Gutierrez M, Borden KLB (2004) Phosphorylation of the eukaryotic translation initiation factor eIF4E contributes to its transformation and mRNA transport activities. Can Res 64:8639–8642

    Article  CAS  Google Scholar 

  41. Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KLB (2005) eIF4E promotes nuclear export of cyclin D1 mRNAs via an element in the 3′UTR. J Cell Biol 169:245–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Culjkovic B, Topisirovic I, Borden KLB (2007) Controlling gene expression through RNA regulons: the role of the eukaryotic translation initiation factor eIF4E. Cell Cycle 6:65–69

    Article  CAS  PubMed  Google Scholar 

  43. Robichaud N, del Rincon SV, Huor B, Alain T, Petruccelli A, Hearnden J, Goncalves C, Grotegut S, Spruck CH, Furic L, Larsson O, Miller WH, Sonenberg N (2015) Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3. Oncogene 34:2032–2042

    Article  CAS  PubMed  Google Scholar 

  44. Zhang H, Ma Y, Zhang S, Liu H, He H, Li N, Gong Y, Zhao S, Jiang J-D, Shao R-G (2015) Involvement of Ras GTPase-activating protein SH3 domain-binding protein 1 in the epithelial-to-mesenchymal transition-induced metastasis of breast cancer cells via the Smad signaling pathway. Oncotarget 6(19):17039

    Article  PubMed  PubMed Central  Google Scholar 

  45. Dou N, Chen J, Yu S, Gao Y, Li Y (2016) G3BP1 contributes to tumor metastasis via upregulation of Slug expression in hepatocellular carcinoma. Am J Cancer Res 6:2641–2650

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Joshi S, Kaur S, Redig AJ, Goldsborough K, David K, Ueda T, Watanabe-Fukunaga R, Baker DP, Fish EN, Fukunaga R, Platanias LC (2009) Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses. Proc Natl Acad Sci 106:12097–12102

    Article  PubMed  Google Scholar 

  47. Martin S, Bellora N, González-Vallinas J, Irimia M, Chebli K, de Toledo M, Raabe M, Eyras E, Urlaub H, Blencowe BJ, Tazi J (2016) Preferential binding of a stable G3BP ribonucleoprotein complex to intron-retaining transcripts in mouse brain and modulation of their expression in the cerebellum. J Neurochem 139:349–368

    Article  CAS  PubMed  Google Scholar 

  48. Reynolds A, Anderson EM, Vermeulen A, Fedorov Y, Robinson K, Leake D, Karpilow J, Marshall WS, Khvorova A (2006) Induction of the interferon response by siRNA is cell type- and duplex length-dependent. RNA 12:988–993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bridge AJ, Pebernard S, Ducraux A, Nicoulaz A-L, Iggo R (2003) Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet 34:263

    Article  CAS  PubMed  Google Scholar 

  50. Tourrière H, Gallouzi I-E, Chebli K, Capony JP, Mouaikel J, van der Geer P, Tazi J (2001) RasGAP-associated endoribonuclease G3BP: selective RNA degradation and phosphorylation-dependent localization. Mol Cell Biol 21:7747–7760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tourrière H, Chebli K, Zekri L, Courselaud B, Blanchard JM, Bertrand E, Tazi J (2003) The RasGAP-associated endoribonuclease G3BP assembles stress granules. J Cell Biol 160:823–831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Atlas R, Leah B, Stav S, Irith G (2007) Dynamic association with polysomes during P19 neuronal differentiation and an untranslated-region-dependent translation regulation of the tau mRNA by the tau mRNA-associated proteins IMP1, HuD, and G3BP1. J Neurosci Res 85:173–183

    Article  CAS  PubMed  Google Scholar 

  53. Proud CG (2015) Mnks, eIF4E phosphorylation and cancer. Biochim Biophys Acta 1849:766–773

    Article  CAS  PubMed  Google Scholar 

  54. Shahbazian D, Parsyan A, Petroulakis E, Hershey J, Sonenberg N (2010) eIF4B controls survival and proliferation and is regulated by proto-oncogenic signaling pathways. Cell Cycle 9:4106–4109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Osborne MJ, Borden KLB (2015) The eukaryotic translation initiation factor eIF4E in the nucleus: taking the road less traveled. Immunol Rev 263:210–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Michlewski G, Cáceres JF (2010) RNase-assisted RNA chromatography. RNA 16:1673–1678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Griffith Institute for Drug Discovery, 46 Don Young Road, Nathan, QLD, 4111, Australia

    Umber Alam & Derek Kennedy

  2. School of Environment and Sciences, Griffith University, Brisbane, QLD, 4111, Australia

    Umber Alam & Derek Kennedy

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11010_2019_3562_MOESM1_ESM.pptx

Figure S1. Expression of MDR-1 protein in MDR.MCF7 cells and MCF7 cells. After long-term treatment with CDDP and 5-FU of MCF7 cells, the RI index of CDDP and 5-FU treated cells were measured against normal MCF7 cells (as described in materials and methods). Then to further confirm the treated cells have become multidrug resistant, the cell extracts were collected to analyse the expression of MDR-1 protein in MDR.MCF7 cells as compared with MCF7 cells. β-Actin was used as an internal control. Figure S2. Half-lives of G3BP1, G3BP2, IFITM1 and IFITM3. IFNα-treated MCF7 cells were treated with 10 μM of CHX for the indicated time points and cell extracts were collected to analyse the half-lives of these proteins. β-Actin was used as an internal control. The immunoblot analysis shows that the expression of G3BP1, G3BP2, IFITM1, IFITM3 and β-Actin after CHX treatment as labelled. Supplementary material 1 (PPTX 254 kb)

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Alam, U., Kennedy, D. G3BP1 and G3BP2 regulate translation of interferon-stimulated genes: IFITM1, IFITM2 and IFITM3 in the cancer cell line MCF7. Mol Cell Biochem 459, 189–204 (2019). https://doi.org/10.1007/s11010-019-03562-3

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