Investigation of Aberrant Translational Regulation of c-myc in Multiple Myeloma
The work of my laboratory has been directed towards investigation of the translation regulation of c-myc. We have shown that the 5' UTR of the c-myc gene contains an internal ribosome entry segment (IRES) and demonstrated that c-myc mRNA can be translated in cap-dependent as well as cap-independent manner [1].We have found that in MM cell lines there is aberrant translation regulation of c-myc (leading to over-production of this protein), and this correlates with a specific mutation in the region of DNA which encodes the IRES [2].
We have shown that a different repertoire of proteins binds to the sequence which harbours the mutation and that all RNA binding proteins interact more strongly with the mutant sequence [3].
We have investigated the occurrence of the mutation in the c-myc gene in MM patients and have shown that it is present in 42% of patient samples [4].
We are now determining the effect of the mutation on translation in cell-free systems and in tissue culture, and isolating and cloning the c-myc exon 1 mRNA binding proteins.
References
1 Stoneley M, Paulin FE, Le Quesne JP, Chappell SA, Willis AE. c-myc 5' untranslated region contains an internal ribosome entry segment. Oncogene 1998 Jan 22;16(3):423-8.
2 Paulin FE, West MJ, Sullivan NF, Whitney RL, Lyne L, Willis AE. Aberrant translational control of the c-myc gene in multiple myeloma. Oncogene 1996 Aug 1;13(3):505-13.
3 Paulin FEM, Chappell SA, Willis AE. A single nucleotide change in the c-myc internal ribosome entry segment leads to enhanced binding of a group of protein factors. Nucleic Acids Res 1998 Jul 1;26(13):3097-103.
4 Chappell SA, LeQuesne JP, Paulin FE, deSchoolmeester ML, Stoneley M, Soutar RL, Ralston SH, Helfrich MH, Willis AE. A mutation in the c-myc-IRES leads to enhanced internal ribosome entry in multiple myeloma: a novel mechanism of oncogene de-regulation. Oncogene 2000 Sep 7;19(38):4437-40.