Systematic analysis of the contribution of c-myc mRNA constituents upon cap and IRES mediated translation
-
Christos Meristoudis
, Theoni Trangas, Andromachi Lambrianidou
, Vasilios Papadopoulos , Euthymios Dimitriadis , Nelly Courtis and Panayotis Ioannidis
Abstract
Fine tuning of c-MYC expression is critical for its action and is achieved by several regulatory mechanisms. The contribution of c-myc mRNA regulatory sequences on its translational control has been investigated individually. However, putative interactions have not been addressed so far. The effect of these interactions upon the translatability of monocistronic and bicistronic chimaeric mRNAs, carrying combinations of the c-myc mRNA 5′-untranlated region (UTR), 3′-UTR, and coding region instability element (CRD) was investigated on this study. The presence of the 5′-UTR induced an increase in translatability of 50%. The presence of the CRD element, when in frame, reduced translatability by approximately 50%, regardless of the expression levels of the wild type CRD- binding protein (CRD-BP/IMP1). Conversely, overexpression of a mutated CRD-BP/IMP1 (Y396F) further impeded translation of the chimaeric mRNAs carrying its cognate sequences. The presence of the c-myc 3′-UTR increased translatability by approximately 300% affecting both cap and c-myc internal ribosome entry site (IRES) mediated translation. In addition, 3′-UTR rescued the cap mediated translation in the presence of the polyadenylation inhibitor cordycepin. Furthermore, the 3′-UTR rescued cap mediated translation under metabolic stress conditions and this was enhanced in the absence of a long poly (A) tail.
Acknowledgments
The authors wish to thank Dr. Antonis Koromilas for critical review of this manuscript. This work was supported by the Greek Ministry of Health and the Hellenic Anticancer Institute.
References
Bernstein, P.L., Herrick, D.J., Prokipcak, R.D., and Ross, J. (1992). Control of c-myc mRNA half-life in vitro by a protein capable of binding to a coding region stability determinant. Genes Dev. 6, 642–654.10.1101/gad.6.4.642Search in Google Scholar
Brewer, G. (1991). An A+U-rich element RNA-binding factor regulates c-myc mRNA stability in vitro. Mol. Cell. Biol. 5, 2460–2466.Search in Google Scholar
Chen, J. and Kastan, M.B. (2010). 5′-3′-UTR interactions regulate p53 mRNA translation and provide a target for modulating p53 induction after DNA damage. Genes Dev. 24, 2146–2156.10.1101/gad.1968910Search in Google Scholar
Chung, H.J. and Levens, D. (2005). c-myc expression: keep the noise down! Mol. Cell 20, 157–166.Search in Google Scholar
Connolly, E., Braunstein, S., Formenti, S., and Schneider, R.J. (2006). Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells. Mol. Cell Biol. 26, 3955–3965.10.1128/MCB.26.10.3955-3965.2006Search in Google Scholar
Di Giammartino, D.C., Shi, Y., and Manley, J.L. (2013). PARP1 Represses PAP and Inhibits Polyadenylation during Heat Shock. Mol. Cell 49, 7–17.10.1016/j.molcel.2012.11.005Search in Google Scholar
Fähling, M., Mrowka, R., Steege, A., Nebrich, G., Perlewitz, A., Persson, P.B., and Thiele, B.J. (2006). Translational control of collagen prolyl 4-hydroxylase-alpha(I) gene expression under hypoxia. J. Biol. Chem. 281, 26089–26101.10.1074/jbc.M604939200Search in Google Scholar
Fiszer-Kierzkowska A., Vydra, N., Wysocka-Wycisk, A., Kronekova, Z., Jarząb, M., Katarzyna, M., Lisowska, K.M., and Krawczyk, Z. (2011). Liposome-based DNA carriers may induce cellular stress response and change gene expression pattern in transfected cells. BMC Mol. Biol. 12, 27–36.10.1186/1471-2199-12-27Search in Google Scholar
Guo, L., Allen, E.M., and Miller, W.A. (2001). Base-pairing between untranslated regions facilitates translation of uncapped, nonpolyadenylated viral RNA. Mol. Cell 7, 1103–1109.10.1016/S1097-2765(01)00252-0Search in Google Scholar
Holcik, M. and Sonenberg, N. (2005). Translational control in stress and apoptosis. Nature Rev. Mol. Cell Biol. 6, 318–327.10.1038/nrm1618Search in Google Scholar PubMed
Hüttelmaier, S., Zenklusen, D., Lederer, M., Dictenberg, J., Lorenz, M., Meng, X., Bassell, G.J., Condeelis, J., and Singer, R.H. (2005). Spatial regulation of β-actin translation by Src-dependent phosphorylation of ZBP. Nature 438, 512–515.10.1038/nature04115Search in Google Scholar PubMed
Ioannidis, P., Courtis, N., Havredaki, M., Michailakis, E., Tsiapalis, C.M., and Trangas, T. (1999). The polyadenylation inhibitor cordycepin (3′dA) causes a decline in c-myc mRNA levels without affecting c-MYC protein levels. Oncogene 8, 117–125.10.1038/sj.onc.1202255Search in Google Scholar PubMed
Johannes, G. and Sarnow, P. (1998). Cap-independent polysomal association of natural mRNAs encoding c-myc, BiP, and eIF4G conferred by internal ribosome entry sites. RNA 4, 1500–1513.10.1017/S1355838298981080Search in Google Scholar PubMed PubMed Central
Kadomatsu, M., Nakajima, S., Kato, H., Gu, L., Chi, Y., Yao, J., and Kitamura, M. (2012). Cordycepin as a sensitizer to tumour necrosis factor (TNF)-α-induced apoptosis through eukaryotic translation initiation factor 2α (eIF2α)- and mammalian target of rapamycin complex 1 (mTORC1)-mediated inhibition of nuclear factor (NF)-κB. Clin. Exp. Immunol. 168, 325–332.10.1111/j.1365-2249.2012.04580.xSearch in Google Scholar PubMed PubMed Central
Kaufman, R.J. (2004). Regulation of mRNA translation by protein folding in the endoplasmic reticulum. Trends Biochem. Sci. 29, 152–158.10.1016/j.tibs.2004.01.004Search in Google Scholar PubMed
Kim, J.H., Kim, T.D., Hahm, B., Kim, K.T., and Jang, S.K. (2003). Heterogeneous nuclear ribonucleoprotein C modulates translation of c-myc mRNA in a cell cycle phase-dependent manner. Mol. Cell. Biol. 23, 708–720.10.1128/MCB.23.2.708-720.2003Search in Google Scholar PubMed PubMed Central
Kim, H.H., Kuwano, Y., Srikantan, S., Lee, E.K., Martindale, J.L., and Gorospe, M. (2009). HuR recruits let-7/RISC to repress c-Myc expression. Genes Dev. 23, 1743–1748.10.1101/gad.1812509Search in Google Scholar PubMed PubMed Central
Lemm, I. and Ross, J. (2002). Regulation of c-myc mRNA decay by translational pausing in a coding region instability determinant. Mol. Cell. Biol. 22, 3959–3969.10.1128/MCB.22.12.3959-3969.2002Search in Google Scholar PubMed PubMed Central
Levens, D. (2010). You don’t muck with MYC. Genes Cancer 1, 547–554.10.1177/1947601910377492Search in Google Scholar PubMed PubMed Central
Liao, B., Hu, Y., and Brewer, G. (2007). Competitive binding of AUF1 and TIAR to MYC mRNA controls its translation. Nat. Struct. Mol. Biol. 14, 511–518.10.1038/nsmb1249Search in Google Scholar PubMed
Muaddi, H., Majumder, M., Peidis, P., Papadakis, A.I., Holcik, M., Scheuner, D., Kaufman, R.J., Hatzoglou, M., and Koromilas, A.E. (2010). Phosphorylation of eIF2α at serine 51 is an important determinant of cell survival and adaptation to glucose deficiency. Mol. Biol. Cell 21, 3220–3231.10.1091/mbc.e10-01-0023Search in Google Scholar PubMed PubMed Central
Nielsen, J., Christiansen, J., Lykke-Andersen, J., Johnsen, A.H., Wewer, U.M., and Nielsen, F.C. (1999). A family of insulin-like growth factor II mRNA binding proteins represses translation in late development. Mol. Cell. Biol. 19, 1262–1270.10.1128/MCB.19.2.1262Search in Google Scholar PubMed PubMed Central
Noubissi, F.K. and Elcheva, I. (2006). CRD-BP mediates stabilization of betaTrCP1 and c-myc mRNA in response to beta-catenin signalling. Nature 441, 898–901.10.1038/nature04839Search in Google Scholar PubMed
Okuyama, H., Endo, H., Akashika,T., Kato, K., and Inoue, M. (2010). Downregulation of c-MYC protein levels contributes to cancer cell survival under dual deficiency of oxygen and glucose. Cancer Res. 70, 10213–10223.10.1158/0008-5472.CAN-10-2720Search in Google Scholar PubMed
Peterson, C.W. and Ayer, D.E. (2011). An extended Myc network contributes to glucose homeostasis in cancer and diabetes. Front. Biosc. 16, 2206–2223.10.2741/3848Search in Google Scholar PubMed
Shi, Y., Frost, P., Hoang, B., Benavides, A., Gera, J., and Lichtenstein A. (2011). IL-6-induced enhancement of c-Myc translation in multiple myeloma cells: critical role of cytoplasmic localization of the RNA-binding protein hnRNP A1. J. Biol. Chem. 286, 67–78.10.1074/jbc.M110.153221Search in Google Scholar PubMed PubMed Central
Shim, H., Chun, Y.S., Lews, B.C., and Dang, C.V. (1998). A Unique glucose depended apoptotic pathway induced by c-myc. Proc. Natl. Acad. Sci. USA 95, 511–516.10.1073/pnas.95.4.1511Search in Google Scholar PubMed PubMed Central
Spriggs, K.A., Stoneley, M., Bushell, M., and Willis, A.E. (2008). Re-programming of translation following cell stress allows IRES mediated translation to predominate. Biol. Cell 100, 27–38.10.1042/BC20070098Search in Google Scholar PubMed
Stoneley, M., Chappell, S.A., Jopling, C.L., Dickens, M., McFarlane, M., and Willis, A.E. (2000). c-Myc protein synthesis is initiated from the internal ribosome entry segment during apoptosis. Mol. Cell. Biol. 20, 1162–1169.10.1128/MCB.20.4.1162-1169.2000Search in Google Scholar PubMed PubMed Central
Subkhankulova, T., Mitchell, S.A., and Willis, A.E. (2001). Internal ribosome entry segment-mediated initiation of c-Myc protein synthesis following genotoxic stress. Biochem. J. 359, 183–192.10.1042/bj3590183Search in Google Scholar
Thoma, C., Bergamini, G., Galy, B., Hundsdoerfer, P., and Hentze, M.W. (2004). Enhancement of IRES-mediated translation of the c-myc and BiP mRNAs by the poly(A) tail is independent of intact eIF4G and PABP. Mol. Cell 15, 925–935.10.1016/j.molcel.2004.08.021Search in Google Scholar PubMed
Thoma, C., Fraterman, S., Gentzel, M., Wilm, M., and Hentze, M.W. (2008). Translation initiation by the c-myc mRNA internal ribosome entry sequence and the poly(A) tail. RNA 14, 1579–1589.10.1261/rna.1043908Search in Google Scholar PubMed PubMed Central
Thomas, L.R. and Tansey, W.P. (2011). Proteolytic control of the oncoprotein transcription factor Myc. Adv. Cancer Res. 110, 77–106.10.1016/B978-0-12-386469-7.00004-9Search in Google Scholar PubMed
Vervoorts, J., Lüscher-Firzlaff, J., and Lüscher, B. (2006). The ins and outs of MYC regulation by posttranslational mechanisms. J. Biol. Chem. 281, 34725–34729.10.1074/jbc.R600017200Search in Google Scholar PubMed
Weidensdorfer, D., Stöhr, N., Baude, A., Lederer, M., Köhn, M., Schierhorn, A., Buchmeier, S., Wahle, E., and Hüttelmaier, S. (2009). Control of c-myc mRNA stability by IGF2BP1-associated cytoplasmic RNPs. RNA 15, 104–115.10.1261/rna.1175909Search in Google Scholar PubMed PubMed Central
Wong, Y.Y., Moon, A., Duffin, R., Barthet-Barateig, A., Meijer, H.A., Clemens, M.J., and de Moor, C.H. (2010). Cordycepin inhibits protein synthesis and cell adhesion through effects on signal transduction. J. Biol. Chem. 285, 2610–2621.10.1074/jbc.M109.071159Search in Google Scholar PubMed PubMed Central
Zhang, X., Virtanen, A., and Kleiman, F.E. (2010). To polyadenylate or to deadenylate. That is the question. Cell Cycle 9, 4437–4449.10.4161/cc.9.22.13887Search in Google Scholar PubMed PubMed Central
©2015 by De Gruyter
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Articles in the same Issue
- Frontmatter
- Reviews
- The intersection between viral oncolysis, drug resistance, and autophagy
- What can lipidomics tell us about the pathogenesis of Alzheimer disease?
- Minireview
- The role of the Lowe syndrome protein OCRL in the endocytic pathway
- Research Articles/Short Communications
- Genes and Nucleic Acids
- Systematic analysis of the contribution of c-myc mRNA constituents upon cap and IRES mediated translation
- Protein Structure and Function
- The double mutation L109M and R448M of HIV-1 reverse transcriptase decreases fidelity of DNA synthesis by promoting mismatch elongation
- The role of Bni5 in the regulation of septin higher-order structure formation
- Cell Biology and Signaling
- Extracellular localization of catalase is associated with the transformed state of malignant cells
- The importin α/β-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways
- Proteolysis
- Inactivation of human kininogen-derived antimicrobial peptides by secreted aspartic proteases produced by the pathogenic yeast Candida albicans
- Corrigendum
- Corrigendum to: Potential importance of Maackia amurensis agglutinin in non-small cell lung cancer