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Molecular and Cellular Biology, February 2000, p. 1162-1169, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

c-Myc Protein Synthesis Is Initiated from the Internal Ribosome Entry Segment during Apoptosis

Mark Stoneley,1,dagger Stephen A. Chappell,1,Dagger Catherine L. Jopling,1 Martin Dickens,1 Marion MacFarlane,2 and Anne E. Willis1,*

Department of Biochemistry, University of Leicester, Leicester LE1 7RH,1 and MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN,2 United Kingdom

Received 14 July 1999/Returned for modification 8 September 1999/Accepted 9 November 1999

Recent studies have shown that during apoptosis protein synthesis is inhibited and that this is in part due to the proteolytic cleavage of eukaryotic initiation factor 4G (eIF4G). Initiation of translation can occur either by a cap-dependent mechanism or by internal ribosome entry. The latter mechanism is dependent on a complex structural element located in the 5' untranslated region of the mRNA which is termed an internal ribosome entry segment (IRES). In general, IRES-mediated translation does not require eIF4E or full-length eIF4G. In order to investigate whether cap-dependent and cap-independent translation are reduced during apoptosis, we examined the expression of c-Myc during this process, since we have shown previously that the 5' untranslated region of the c-myc proto-oncogene contains an IRES. c-Myc expression was determined in HeLa cells during apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. We have demonstrated that the c-Myc protein is still expressed when more than 90% of the cells are apoptotic. The presence of the protein in apoptotic cells does not result from either an increase in protein stability or an increase in expression of c-myc mRNA. Furthermore, we show that during apoptosis initiation of c-myc translation occurs by internal ribosome entry. We have investigated the signaling pathways that are involved in this response, and cotransfection with plasmids which harbor either wild-type or constitutively active MKK6, a specific immediate upstream activator of p38 mitogen-activated protein kinase (MAPK), increases IRES-mediated translation. In addition, the c-myc IRES is inhibited by SB203580, a specific inhibitor of p38 MAPK. Our data, therefore, strongly suggest that the initiation of translation via the c-myc IRES during apoptosis is mediated by the p38 MAPK pathway.

* Corresponding author. Mailing address: Department of Biochemistry, University of Leicester, University Rd., Leicester LE1 7RH, United Kingdom. Phone: 0116 2523363. Fax: 0116 2523369. E-mail: aew5{at}le.ac.uk.

dagger Present address: School of Biochemistry and Molecular Biology, The University of Leeds, Leeds LS2 9JT, United Kingdom.

Dagger Present address: Department of Neurobiology, The Scripps Research Institute, La Jolla, CA 92037.

Molecular and Cellular Biology, February 2000, p. 1162-1169, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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