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

Cobbold, L.C., Wilson, L.A., Sawicka, K., King, H.A., Kondrashov, A.V., Spriggs, K.A., Bushell, M. and Willis, A.E. (2010) 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(19), pp. 2884-2891. (doi: 10.1038/onc.2010.31) (PMID:20190818)

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.

• Item Type: Articles
• Additional Information: 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.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bushell, Professor Martin
• Authors: Cobbold, L.C., Wilson, L.A., Sawicka, K., King, H.A., Kondrashov, A.V., Spriggs, K.A., Bushell, M., and Willis, A.E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncogene
• Publisher: Springer Nature
• ISSN: 0950-9232
• ISSN (Online): 1476-5594
• Published Online: 01 March 2010