Functional Analysis of a Naturally Occurring Mutant myc Gene

Gallagher, Ronald Charles John (1996) Functional Analysis of a Naturally Occurring Mutant myc Gene. PhD thesis, University of Glasgow.

Abstract

The c-myc gene plays a role in the aetiology of various cancers of humans and animals. Feline leukaemia virus has also been demonstrated to have oncogenic potential, and in approximately one third of tumours where FeLV is present aberrant expression of a myc gene occurs. This changed expression pattern is mainly due to FeLV transduction of the myc gene, but can also occur by insertional mutagenesis. Until recently v-myc genes have been found to be virtually equivalent to c-myc, with few mutations in the coding sequence. This project focuses on a FeLV-transduced v-myc, termed T17-myc, which is exceptional in that it is highly mutated. Mutations include partial loss of a domain previously identified as crucial for transformation, as well as an insertion in the basic region (BR) sequence-specific DNA binding domain. The aim of this work was to characterise the mutant oncogene at the biological and biochemical level, to discover whether various Myc functions could be dissociated using the mutant. I have shown that the original mutations are maintained in secondary lymphomas which occurred rapidly after inoculation of the T17 virus complex, arguing that the mutant is a relatively efficient oncogene. Despite its apparent in vivo efficiency, it was transformation defective in chick embryo fibroblasts, and was unable to induce apoptosis in the same cells. Chimaeric genes showed that the transformation and apoptosis defects were caused by the N-terminal mutation. However, the C-terminal BR mutation independently lowered transformation efficiency and growth rate, although the mutation did not prevent binding to DNA along with Max, either in vitro or in vivo. Analysis of gene expression in the original T17 lymphoma-derived cell line showed that putative Myc regulated, and Myc regulating genes were expressed in the mutant Myc cell line, although the mutant Myc was able to interact with the transcriptional repressor pi07 in vitro. The data presented in this thesis are consistent with a model where mutations in the N-terminal domain of Myc abolish the negative growth effects of the myc gene, with relatively little consequence for its oncogenic function in T cells. Also consistent with these data is the ability of Myc to interact with cell type specific factors involved in transcription of Myc-regulated genes.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: R Fulton
• Keywords: Genetics
• Date of Award: 1996
• Depositing User: Enlighten Team
• Unique ID: glathesis:1996-74863
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 27 Sep 2019 15:47
• Last Modified: 27 Sep 2019 15:47
• URI: https://theses.gla.ac.uk/id/eprint/74863