Internal ribosome entry in the myc gene family
thesisposted on 15.12.2014, 10:32 by Catherine L. Jopling
The proto-oncogene c-myc is encoded by a transcript in which the 5' UTR contains a potent internal ribosome entry segment (IRES). The N-myc gene shows considerable homology to c-myc and also possesses a 5' UTR that is long and structured. Thus, the potential for internal ribosome entry within this UTR was examined. N-myc was found to contain an IRES that was of comparable activity to that of c-myc in non-neuronal cells, but was specifically activated relative to the c-myc IRES in neuronal cells in which the N-myc transcription is expressed. Furthermore, the activity of the N-myc IRES was specifically inhibited during neuronal differentiation, when N-myc expression is reduced. The trans-acting factor requirements for N-myc IRES function were examined and a candidate protein was found, although not characterised.;An IRES was also identified in the 5' UTR of the third well-studied member of the myc gene family, L-myc. An alternative form of the UTR exists in which an intron is retained, but it was not possible to draw any definite conclusions on the IRES activity of this UTR.;Translation of both c- and N-myc mRNAs can occur by both cap-dependent and IRES-dependent mechanisms, so the existence of IRESs within these transcripts was intriguing. c-Myc protein levels were analysed during apoptosis and were maintained, despite the apoptotic inhibition of protein synthesis and the short half-life of c-Myc. The activity of the c-myc IRES was maintained during apoptosis and was responsible for this effect. The c-myc IRES was also shown to lie downstream of the p38 mitogen-activated protein kinase signalling pathway.