The deregulation of RNA polymerases I and III in tumours

Daly, Nicole Louise (2004) The deregulation of RNA polymerases I and III in tumours. PhD thesis, University of Glasgow.

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Abstract

RNA polymerases I and III are responsible for approximately 80% of all nuclear transcription. The activity of these enzymes is a major determinant of the biosynthetic capacity of cells, since they synthesise important products required for protein synthesis, such as tRNAs and rRNAs. Regulation of these polymerases is likely to be of fundamental importance, since their activity is controlled directly by two cardinal tumour suppressors, RB and p53. Cervical, breast and colorectal malignancies were investigated to assess if activity of RNA polymerases I and III is deregulated in these cancers. Expression studies of genes transcribed by these polymerases demonstrated that most of the tumour biopsies examined displayed deregulated transcriptional activity in comparison with matched normal tissue. In the cervical biopsy samples examined, the presence of human papillomavirus 16 correlated with dramatic and specific overexpression of genes transcribed by these polymerases. This may be explained by the fact that, upon integration into the host genome, this virus upregulates the levels of the oncoproteins E6 and E7, which are able to neutralise p53 and RB, respectively. Furthermore, Brf1, a subunit of TFIIIB, was also found to be overexpressed, and this correlated with the increased levels of RNA polymerase III transcripts in the human papillomavirus 16 infected samples. This subunit was also found to be elevated in some cases of the other tumour types tested. When other factors were investigated that may contribute to upregulated rates of transcription, it was found that in the breast tumour biopsies, upregulation of c-Myc closely correlated with increased levels of RNA polymerase I transcripts as well as MRP and 7SK transcripts. In the colon tumour biopsies, a correlation was observed between the c-Myc target, cyclin D2, and increased levels of RNA polymerase III transcripts. It was also found through comparison of a transformed and untransfomed cell line that RNA polymerase III transcription may be regulated through acetylation and deacetylation.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Robert J White
Keywords: Biochemistry
Date of Award: 2004
Depositing User: Enlighten Team
Unique ID: glathesis:2004-71231
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 10:49
Last Modified: 10 May 2019 10:49
URI: http://theses.gla.ac.uk/id/eprint/71231

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