Regulation of E2F through the DP component

Cruickshank, Amanda Jayne Mary (2000) Regulation of E2F through the DP component. PhD thesis, University of Glasgow.

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Abstract

Transcription factor E2F plays an important role in orchestrating early cell cycle progression through its ability to co-ordinate and integrate the cell cycle with the transcriptional apparatus. Physiological E2F arises when members of two distinct families interact as E2F-DP heterodimers, in which the E2F component mediates transcriptional activation and physical interaction with pocket proteins, such as the tumour suppressor protein pRB. However, very little information is available regarding the mechanisms, which control the levels of functional E2F. In this study I have defined the DP component as an integrator of the E2F transcription factor with the nuclear transport pathway and the ubiquitin-proteasome mediated degradation pathway. Specifically, a bipartite nuclear localisation signal in DP is defined and shown to be necessary for nuclear accumulation of a non-NLS-containing heterodimeric partner. Pocket protein association also offers an alternative in trans NLS for translocation of the heterodimer into the nucleus. Surprisingly, the basic region of the NLS is also necessary for efficient nuclear accumulation of NLS-containing E2F heterodimeric partners. The basic region is also instrumental in the association of DP-3 with the epsilon isoform of the 14-3-3 family of signalling molecules. Using a mutant DP that fails to bind 14-3-3 has uncovered a role for 14-3-3 in the E2F pathway. An association targets the E2F heterodimer for ubiquitin-proteasome-mediated degradation to reduce excessive levels of E2F and allow cells to progress into G2 phase of the cell cycle. This study defines new pathways of growth control that are integrated with the E2F pathway through the DP subunit.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Nicholas B La Thangue
Keywords: Cellular biology
Date of Award: 2000
Depositing User: Enlighten Team
Unique ID: glathesis:2000-71227
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/71227

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