Abstract
eIF4E is essential for translation initiation, but its overexpression causes malignant transformation. Recent work demonstrated that eIF4E/F participates in exposing and locating alternate translation start codons during scanning. Translation initiation of several important protooncogenes and growth-regulators, such as Myc and FGF-2, can start at CUG start codon(s) upstream of the normal open reading frame (ORF). The resulting amino-terminal extension alters the properties of these proteins and their intracellular distribution. In cells overexpressing eIF4E, c-myc is overexpressed and particularly the larger, CUG-initiated form (Myc1). Recent reports suggest that synthesis of Myc2, the normally expressed AUG-initiated form, is mediated by an IRES. To determine what role eIF4E might play in c-myc expression, the c-myc 5′ untranslated region (UTR) was fused in-frame to CAT reporters, and several more derivative constructs were made. In vitro translation experiments (with and without eIF4E/F); expression in CHO cells transformed with eIF4E; and deletion/mutation analysis demonstrated that Myc1 is translated by a scanning mechanism, while Myc2 is translated by Internal Ribosome Repositioning. Moreover, the existence of a true IRES in the 5′UTR was contradicted by its failure to direct translation of a circular transcript, in contrast to hsp70. The c-myc 5′UTR also failed to engage in translation in the absence of functional eIF4F, after cleavage of the eIF4G component with CVB4 protease-2A. The Internal Repositioning Element (IRPE) in c-myc 5′UTR was delimited to nucleotides (nt) 394 – 440 from the P1 transcription start site.
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References
Acland P, Dixon M, Peters G and Dickson C. . 1990 Nature 343: 662–665.
Ar-Rushdi A, Nishakura K, Erickson J, Watt R, Rovera G and Croce C. . 1983 Science 222: 390–393.
Bentley DL and Groudine M. . 1986 Nature 321: 702–706.
Borman AW and Kean KM. . 1997 Virology 237: 129–136.
Chen CY and Sarnow P. . 1995 Science 268: 415–417.
Clemens MJ. . 1987 In: Transcription and Translation: A practical approach, Rickwood D and Hanes BD (eds).. IRL Press Ltd. Oxford pp. 263–276.
Dalla-Favera R, Baregni M, Erikson J, Patterson D, Gallo RC and Croce C. . 1982 Proc. Natl. Acad. Sci. USA 79: 7824–7827.
De Benedetti A, Joshi-Barve S, Rinker-Schaeffer CW and Rhoads RE. . 1991 Mol. Cell. Biol. 11: 5435–5445.
De Benedetti A, Joshi-Barve S, Graff JR and Zimmer SG. . 1994 Mol. Cell. Diff. 2: 347–371.
Dosaka-Akita H, Rosenberg RK, Minna JD and Birrer MJ. . 1991 Oncogene 6: 371–378.
Florkiewicz RZ and Sommer A. . 1989 Proc. Natl. Acad. Sci. USA 86: 3978–3981.
Fraser SD, Wilkes-Johnston J and Browder LW. . 1996 Oncogene 12: 1223–1230.
Fütterer J, Kiss-László Z and Hohn T. . 1993 TIBS 22: 177–181.
Gandori C and Eisenman RN. . 1997 TIBS 22: 177–181.
Hann SR, Dixit M, Sears RC and Sealy L. . 1994 Gene Dev. 8: 2441–2452.
Hann SR, King MW, Betley DL, Anderson CW and Eisenman RN. . 1988 Cell 52: 185–195.
Jackson RJ. . 1996 In: Translational Control, Hershey JWB, Mathews MB and Sonenberg N, Rickwood D and Hanes BD (eds).. Cold Spring Harbor: Cold Spring Harbor Laboratory Press pp. 71–112.
Joshi-Barve S, De Benedetti A and Rhoads RE. . 1992 J. Biol. Chem. 267: 21038–21043.
Kevil C, Carter P Hu B and De Benedetti A. . 1995 Oncogene 11: 2339–2348.
Koromilas AE, Lazaris-Karatzas A and Sonenberg N. . 1992 EMBO J. 11: 4153–4158.
Kozak M. . 1978 Cell 15: 1109–1123.
Kozak M. . 1990 Proc. Natl. Acad. Sci. USA 87: 8301–8305.
Lamphear BJ and Rhoads RE. . 1996 Biochemistry 35: 15726–15733.
Latorre P, Kolakofsky D and Curran J. . 1998 Mol. Cell. Biol. 18: 5021–5031.
Lazarus P. . 1992 Oncogene 7: 1037–1041.
Mellentin JD, Smith SD and Cleary ML. . 1989 Cell 58: 77–83.
Mendez R, Kollmorgen G, White MF and Rhoads RE. . 1997 Mol. Cell. Biol. 17: 5184–5192.
Nanbru C, Lafon I, Audiger S, Gensac M-C, Vagner S, Huez G and Prats A-C. . 1997 J. Biol. Chem. 272: 32061–32066.
Nathan C-A, Carter P, Liu L, Li BD, Abreo F, Tudor A, Zimmer SG and De Benedetti A. . 1997 Oncogene 15: 1087–1094.
Parkin N, Darveau A, Nicoloson R and Sonnenberg N. . 1988 Mol. Cell Biol. 8: 2875–2883.
Paulin FEM, West MJ, Sullivan NF and Willis AE. . 1996 Oncogene 13: 505–513.
Pause A and Sonnenberg N. . 1993 Curr. Opin. Structural Biol. 3: 953–959.
Penn LJZ, Brooks, MW, Laufer, EM and Land H. . 1990 EMBO. J. 9: 1113–1121.
Reddy, KS and Sulcova V. . 1997 Cancer Genet. Cytogenet. 95: 206–209.
Rhoads, RE. . 1993 J. Biol. Chem. 266: 3017–3020.
Saris CM, Domen J and Berns A. . 1991 EMBO J. 10: 655–664.
Stonely M, Paulin FEM, Le Quesne JPC, Chappell SA and Willis AE. . 1998 Oncogene 16: 423–428.
Taub R, Kirsh I, Morton C, Lenoir G, Swan D, Tronick S, Aaronson S and Leder P. . 1982 Proc. Natl. Acad. Sci. USA 79: 7837–7841.
West M, Sullivan NF and Willis AE. . 1995 Oncogene 11: 2515–2524.
West MJ, Stoneley M and Willis AE. . 1998 Oncogene 17: 769–780.
Yueh A and Schneider RJ. . 1996 Gen. Dev. 10: 1557–1567.
Zuker M. . 1989 In: Methods in Enzymology, Dahlberg and Abelson (eds). Academic Press, New York. pp. 262–288.
Acknowledgements
We are indebted to Nissim Hay (University of Chicago) for the human c-myc cDNA; Richard Jackson (University of Cambridge) for the pXLJ – EMC bicistronic construct; Rick Morimoto (Northwestern University) for the human hsp70 cDNA; Bhavesh Joshi (Marine Biotechnology Institute, Baltimore) for the pREP11 construct; Warren Bryce (Abbot Laboratories, North Chicago) for the rabbit c-Myc antiserum; Barry Lamphear (LSUMC) for the CVB4 protease 2A. This work was supported by NSF grant MCB9513756 and NIH grant CA69148-01A1.
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Carter, P., Jarquin-Pardo, M. & De Benedetti, A. Differential expression of Myc1 and Myc2 isoforms in cells transformed by eIF4E: evidence for internal ribosome repositioning in the human c-myc 5′UTR. Oncogene 18, 4326–4335 (1999). https://doi.org/10.1038/sj.onc.1202890
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DOI: https://doi.org/10.1038/sj.onc.1202890
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