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Title: Characterisation of an acetylation-dependent FLIP/Ku70 complex that regulates FLIP expression
Author: Kerr, Emma Mary
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2012
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c-FLlP is a major anti-apoptotic protein that prevents apoptosis mediated by death receptors. c-FLlP binds to the DISC via its tandem DEDs and the DED of FADD and inhibits the processing of procaspases 8 and 10. Overexpression of c-FLlP results in the evasion of apoptosis, a key hallmark of cancer and a major factor in drug resistance. c-FLlP is a critical regulator of cell death, regulating apoptosis induced by death ligands and a range of chemotherapeutic agents. Importantly, normal cells do not appear to rely on c-FLlP for survival to the same extent as cancer cells. c-FLlP is overexpressed in colorectal cancer, and high c-FLlP expression is an independent adverse prognostic marker in stage 11/111 colorectal cancer. c-FLlP is an important determinant of cancer cell survival and drug resistance and inhibition of c-FLlP constitutes a promising therapeutic strategy for the treatment of cancer. Targeting of c-FLlP remains clinically difficult due to a lack of enzyme activity and known crystal structure. We therefore aimed to identify novel binding partners of c-FLlP that regulate c-FLlP expression and my act as a more tractable surrogate target. Ku70, a DNA repair protein, or more specifically the C terminal region from amino acids 430- 496 was identified to interact with c-FLlP, mediated by an arginine residue 122 in DED2 of c-FLlP. We demonstrated that this interaction regulated c-FLlP expression, preventing its ubiquitination and proteasomal degradation. Ku70 is a target for acetyiation, and can be targeted using HDAC inhibitors. Treatment with HDACi increased acetylation of Ku70, dissociating the c-FLlP/Ku70 complex and resulting in degradation of c-FLlP by the UPS and caspase 8 dependent apoptosis. Furthermore, using isoform selective HDACi we determined that HDAC6 was important in regulating the acetylation of Ku70, and therefore involved in regulating c-FLIP expression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available