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Upregulated c-myc expression in multiple myeloma by internal ribosome entry results from increased interactions with and expression of PTB-1 and YB-1

Oncogene volume 29, pages 2884–2891 (2010)Cite this article

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Abstract

The 5′ untranslated region of the proto-oncogene c-myc contains an internal ribosome entry segment (IRES) and c-myc translation can therefore be initiated by internal ribosome entry as well as by cap-dependent mechanisms. It has been shown previously that in patients with multiple myeloma (MM) and in MM-derived cell lines there is a C to T mutation in the c-myc IRES that increases IRES activity and the corresponding synthesis of c-myc protein although it is not fully understood how this occurs. Our data show that two recently identified c-myc IRES trans-acting factors, Y-box binding protein 1 (YB-1) and polypyrimidine tract-binding protein 1 (PTB-1), bind more strongly (approximately 3.5- and 2-fold respectively) to the mutated version of the c-myc IRES and in vitro these proteins exert their effect synergistically to stimulate IRES activity of the mutant IRES 4.5-fold more than the wild-type version. Importantly, we show that there is a strong correlation between the expression of PTB-1, YB-1 and c-myc in MM-derived cell lines, suggesting that by reducing either PTB-1 or YB-1 protein levels it is possible to decrease c-myc expression and inhibit cell proliferation of MM-derived cell lines.

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Acknowledgements

This work was funded by grants from the BBSRC (LCC, HAK) and CRUK (LAW, AVK). Martin Bushell is a BBSRC David Philips fellow and Anne Willis holds a BBSRC professorial fellowship. We thank Professor Dalton (Moffitt Cancer Center, Florida, USA) for providing the cell line 8226/R5.

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  1. Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK

    L C Cobbold, L A Wilson, K Sawicka, H A King, A V Kondrashov, K A Spriggs, M Bushell & A E Willis

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  1. L C Cobbold
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  2. L A Wilson
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  3. K Sawicka
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Correspondence to A E Willis.

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Cobbold, L., Wilson, L., Sawicka, K. et al. Upregulated c-myc expression in multiple myeloma by internal ribosome entry results from increased interactions with and expression of PTB-1 and YB-1. Oncogene 29, 2884–2891 (2010). https://doi.org/10.1038/onc.2010.31

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