CUED Publications database

Internal ribosome entry segment-mediated initiation of c-Myc protein synthesis following genotoxic stress

Subkhankulova, T and Mitchell, SA and Willis, AE (2001) Internal ribosome entry segment-mediated initiation of c-Myc protein synthesis following genotoxic stress. Biochemical Journal, 359. pp. 183-192. ISSN 0264-6021

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Abstract

Initiation of translation of the proto-oncogene c-myc can occur by either the cap-dependent scanning mechanism or by internal ribosome entry. The latter mechanism requires a complex RNA structural element that is located in the 5′ untranslated region of c-myc, termed an internal ribosome entry segment (IRES). Recent work has shown that IRESs are used to maintain protein expression under conditions when cap-dependent translation initiation is compromised; for example, during mitosis, apoptosis and under conditions of cell stress, such as hypoxia or heat shock. Induction of genotoxic stress also results in a large reduction in global protein synthesis rates and therefore we investigated whether the c-myc IRES was active following DNA damage. As expected, in cells treated with either ethylmethane sulphonate or mitomycin C there was a large reduction in protein synthesis, although this was brought about by two different mechanisms. However, in each case the c-myc IRES was active and c-Myc protein expression was maintained. Finally we showed that the proteins required for this process are downstream of the p38 mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated protein kinase (ERK)/MEK(MAPK/ERK kinase) signalling pathways, since pre-treatment of cells with inhibitors of these pathways before DNA damage is initiated inhibits both c-myc IRES activity and expression of c-Myc protein.

Item Type: Article
Uncontrolled Keywords: 5' Untranslated Regions Blotting, Northern Blotting, Western Cell Survival DNA Damage DNA-Binding Proteins Electrophoresis, Polyacrylamide Gel Enzyme Inhibitors Ethyl Methanesulfonate HeLa Cells Humans Immunosuppressive Agents Luciferases Mitogen-Activated Protein Kinases Mitomycin Peptide Chain Initiation, Translational Phosphorylation Precipitin Tests Protein Biosynthesis Protein Kinases Protein Synthesis Inhibitors Proto-Oncogene Proteins c-myc RNA, Messenger Ribosomes Sirolimus TOR Serine-Threonine Kinases Transcription Factors p38 Mitogen-Activated Protein Kinases
Subjects: UNSPECIFIED
Divisions: Div C > Biomechanics
Depositing User: Unnamed user with email sms67@cam.ac.uk
Date Deposited: 27 Oct 2017 20:10
Last Modified: 22 Oct 2019 07:48
DOI: 10.1042/0264-6021:3590183