Transcriptional Regulation and Cell Transformation by v-Jun

Dunn, Catherine Ann (2001) Transcriptional Regulation and Cell Transformation by v-Jun. PhD thesis, University of Glasgow.

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v-Jun, a mutated derivative of the c-Jun transcription factor, is the transforming oncoprotein of an avian sarcoma virus. v-Jun is thought to cause cell transformation and tumorigenesis by the mis-regulation of certain target gene promoters. v-Jun can both activate and repress gene transcription compared to c-Jun, however little is known about the underlying mechanisms and the identity of the critical "effector" target gene(s) responsible for cell transformation and tumorigenesis by v-Jun. To investigate the mechanisms of transcriptional regulation by v-Jun, a comparative study was undertaken of two gene promoters, bkj and collagenase, which are respectively activated or repressed by v-Jun. Promoter mutagenesis experiments were performed to investigate the effects of Jun binding site position and core promoter element sequences on transcriptional regulation by v-Jun. The primary conclusion was that these factors alone did not determine whether target promoters were activated or repressed by v-Jun. However, alterations in the level of transcriptional activation and fold induction of the variant promoters by v-Jun implied that binding site position and core promoter sequences did influence transcriptional regulation by Jun proteins. This analysis also suggested that v-Jun regulated transcription by different mechanisms at different target promoters. Further work investigated the relationship between transcriptional activation of v-Jun target promoters and cell transformation using DeltavJ-hER, an amino-terminally truncated v-Jun protein fused to the hormone-binding domain of estrogen receptor-alpha. This chimaeric protein was previously shown to induce activation of v-Jun target genes and cell transformation in an estradiol-dependent manner, despite lacking the v-Jun transcriptional activation domain. The estrogen receptor activating function-2 (AF-2) domain was proposed to substitute for this v-Jun domain, implying that estradiol-dependent transcriptional activation of v-Jun target gene promoters by AvJ-hER was required for cell transformation. To test this hypothesis, an inactivating mutation was introduced into helix 12 of the AF-2 domain, which mediates estrogen receptor binding to co-activator proteins. The mutant AvJ-hER protein was inactive in transcription and cell transformation assays, confirming that these processes required AF-2 function. Many estrogen receptor co-activator proteins have histone acetyltransferase activity, however the p300 histone acetyltransferase domain was unable to substitute for the estrogen receptor AF-2 domain function to induce either transcriptional activation or cell transformation. In conclusion, while the mechanisms responsible for transcriptional activation and repression by v-Jun remain unclear, these results support the hypothesis that transcriptional activation of positive v-Jun target gene promoters is required for cell transformation.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Dave Gillespie
Keywords: Molecular biology
Date of Award: 2001
Depositing User: Enlighten Team
Unique ID: glathesis:2001-75742
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 18:17
Last Modified: 19 Nov 2019 18:17

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