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Molecular and Cellular Biology, March 2009, p. 1565-1574, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.01283-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Canonical Initiation Factor Requirements of the Myc Family of Internal Ribosome Entry Segments{triangledown} ,{dagger}

Keith A. Spriggs,1,{ddagger} Laura C. Cobbold,1,{ddagger} Catherine L. Jopling,1 Rebecca E. Cooper,1 Lindsay A. Wilson,1 Mark Stoneley,1 Mark J. Coldwell,2 Didier Poncet,3 Ya-Ching Shen,4 Simon J. Morley,2 Martin Bushell,1 and Anne E. Willis1*

School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom,1 School of Life Sciences, University of Sussex, Brighton BN1 6QG, United Kingdom,2 Unite Mixte de Recherche, CNRS 2472-INRA 1157, Virologie Moléculaire et Structurale, Batiment 14B, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette, France,3 School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan4

Received 13 August 2008/ Returned for modification 3 December 2008/ Accepted 26 December 2008

Initiation of protein synthesis in eukaryotes requires recruitment of the ribosome to the mRNA and its translocation to the start codon. There are at least two distinct mechanisms by which this process can be achieved; the ribosome can be recruited either to the cap structure at the 5' end of the message or to an internal ribosome entry segment (IRES), a complex RNA structural element located in the 5' untranslated region (5'-UTR) of the mRNA. However, it is not well understood how cellular IRESs function to recruit the ribosome or how the 40S ribosomal subunits translocate from the initial recruitment site on the mRNA to the AUG initiation codon. We have investigated the canonical factors that are required by the IRESs found in the 5'-UTRs of c-, L-, and N-myc, using specific inhibitors and a tissue culture-based assay system, and have shown that they differ considerably in their requirements. The L-myc IRES requires the eIF4F complex and the association of PABP and eIF3 with eIF4G for activity. The minimum requirements of the N- and c-myc IRESs are the C-terminal domain of eIF4G to which eIF4A is bound and eIF3, although interestingly this protein does not appear to be recruited to the IRES RNA via eIF4G. Finally, our data show that all three IRESs require a ternary complex, although in contrast to c- and L-myc IRESs, the N-myc IRES has a lesser requirement for a ternary complex.

* Corresponding author. Mailing address: School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom. Phone: 44 1158467095. Fax: 44 1158468877. E-mail: anne.willis{at}nottingham.ac.uk

{triangledown} Published ahead of print on 5 January 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} K.A.S. and L.C.C. contributed jointly to this project.

Molecular and Cellular Biology, March 2009, p. 1565-1574, Vol. 29, No. 6
0270-7306/09/$08.00+0     doi:10.1128/MCB.01283-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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