Deregulation of RNA polymerase III transcription in response to polyomavirus transformation

Felton-Edkins, Zoe A (2001) Deregulation of RNA polymerase III transcription in response to polyomavirus transformation. PhD thesis, University of Glasgow.

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Abstract

RNA polymerase (pol) III transcription is stimulated in response to a variety of factors. Numerous studies concerning the DNA tumour virus Simian Virus 40 (SV40) have served to identify mechanisms surrounding its ability to elevate pol III transcriptional activity. Polyomavirus, a close relative of SV40, has similarly been shown to induce abnormally elevated levels of pol III transcription; however, the mechanisms involved were not previously established. This study presents an analysis of the mechanisms employed by Polyomavirus, as well as providing further insight into those utilised by SV40. In untransformed fibroblasts, the basal pol III factor TFIIIB is repressed through association with the retinoblastoma protein RB; this restraint is overcome by the large T antigens of Polyomavirus and SV40. Furthermore, cells transformed by these papovaviruses overexpress the B" subunit of TFIIIB, at both the protein and mRNA levels. Despite the overexpression of B", the abundance of other TFIIIB components, TBP and BRF, is unperturbed following papovavirus transformation. In contrast, all five subunits of the basal factor TFIIIC2 are abnormally abundant in fibroblasts transformed by either Polyomavirus or SV40, as demonstrated by the elevated levels of their mRNAs. Thus, both papovaviruses stimulate pol III transcription by boosting production specifically of selected components of the basal machinery. However, Polyomavirus differs from SV40 in adopting an additional and apparently unique deregulatory mechanism. This study presents the first evidence of a direct increase in pol III itself following viral transformation, as pol III activity and an accompanying elevation in the abundance of pol III subunits are observed following transformation by Polyomavirus. Another important difference of Polyomavirus is its ability to encode a highly oncogenic middle T antigen that is localised outside the nucleus and activates several signal transduction pathways. Like the large T antigen, the middle T antigen can serve as a potent and specific activator of pol III in transfected cells. This may be mediated through the middle T-induced activation of the MAPK pathway, correlating with an increase in the expression of active ERK. Furthermore, an endogenous interaction between ERK and TFIIIB presents the possibility of a direct role for ERK in the stimulation of pol III transcription. Thus, a striking variety of distinct mechanisms contribute to the dramatically elevated levels of pol III transcription that accompany transformation by Polyomavirus and SV40.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Bob White
Keywords: Biochemistry
Date of Award: 2001
Depositing User: Enlighten Team
Unique ID: glathesis:2001-72688
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 11 Jun 2019 11:06
Last Modified: 11 Jun 2019 11:06
URI: http://theses.gla.ac.uk/id/eprint/72688

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