U490770.pdf (17.66 MB)
Download file

To investigate the subcellular localisation of CBP (CREB-binding protein) and its interacting proteins

Download (17.66 MB)
thesis
posted on 15.12.2014, 10:32 by Colm M. Ryan
CBP (Creb-binding Protein) is a histone acetyltransferase that plays an essential role in RNA-polymerase II-dependent transcription.;CBP acetylation of non-histone proteins such as p53, ACTR and Impa has been postulated to regulate their activity. The research described shows the interaction between CBP and the nuclear transport proteins CAS, Impa and the nucleoporin Nup93. We show that increasing global acetylation levels using HDAC inhibitors (HDACi) leads to a perturbation in the subcellular localisation of CAS, while the number of CBP-associated PML bodies increases. In addition, we demonstrate that CBP association with Impa increases in response to HDACi treatment. These results give us a novel insight into the regulation of non-histone proteins by HDACi. In addition, these findings suggest a functional link between chromatin regulation, acetylation and nuclear transport.;Mislocalisation of CBP from PML bodies has been implicated in the pathology of many diseases such as Huntingdon's disease and Acute Myeloid leukaemia expressing the fusion protein MOZ-TIF2. CBP mislocalisation has also been implicated in Kennedy's disease, a late onset neurodegenerative disorder, which expresses a mutant form of the Androgen Receptor (AR) with an expanded polyglutamine region. Reports in the literature suggest that the mislocalisation of CBP in Kennedy's disease may play a crucial role in its pathology. Here we describe experiments, which show that both CBP and PML are mislocalised in cell expressing AR with An expanded polyglutamine tract. Furthermore, we demonstrate that ARQ077-dependent transcriptional repression cannot be rescued by overexpression of CBP in neuronal and non-neuronal cell line. These results shed new light on the potential role of CBP and PML in Kennedy's disease.

History

Date of award

01/01/2006

Author affiliation

Biochemistry

Awarding institution

University of Leicester

Qualification level

Doctoral

Qualification name

PhD

Language

en

Usage metrics

Categories

Keywords

Exports