Lester, KN;
(2014)
Identification of a Role for G Protein-Coupled Receptor Kinase 5 in Regulating Apoptosis.
Doctoral thesis , UCL (University College London).
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Abstract
The G protein-coupled receptor kinases (GRKs) are best known for their role in phosphorylating G protein-coupled receptors (GPCRs). In addition to their canonical role, the GRKs have a number of non-receptor substrates and binding partners. GRK5 contains functional nuclear localisation and export sequences and many newly discovered binding partners of the kinase are, indeed, nuclear. My thesis outlines the discovery of novel nuclear GRK5 binding partners, class I histone deacetylases (HDACs), HDACs 1, 3 and 8, as well as the repressor protein, Swi-independent 3 (Sin3) A, and reports a role for GRK5 in regulating B cell lymphoma protein 2 (Bcl-2) gene transcription in conjunction with this repressor complex. Attempts to map the HDAC1 and Sin3A binding sites on GRK5 were carried out using GRK5 peptide arrays. Suspected GRK5 residues involved in binding were identified and mutated, but no viable binding deficient mutants were identified. Using HDAC and Sin3A inhibitors, I show GRK5 to negatively regulate Bcl-2 transcription in a class I HDAC and, most likely, a Sin3A dependent manner. Bcl-2, an anti-apoptotic protein, is upregulated in the early stages of many colorectal cancers (CRCs) and is, at least in part, responsible for the apoptotic resistance of metastatic CRCs. Notably, GRK5 expression levels are low in the colon cancer cell line, HT-29, in comparison to other tumour-derived cancer cell lines and overexpressing the kinase in HT-29 cells by cDNA transfection increases the susceptibility of these cells to chemotherapeutically induced apoptosis. Furthermore, overexpression of an inhibitor of miR-135a, a micro RNA (miRNA) that is upregulated in CRC, increases endogenous GRK5 expression as well as apoptosis in HT-29 cells, highlighting the potential use of a miR-135a inhibitor as a novel therapeutic strategy to treat CRC patients.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Identification of a Role for G Protein-Coupled Receptor Kinase 5 in Regulating Apoptosis |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1418752 |
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