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Title: Identification and functional analysis of novel components of the TRAIL apoptosis signalling pathway
Author: Falschlehner, Christina
ISNI:       0000 0004 2706 2623
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2009
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Apoptosis, a controlled form of cell death, plays a central role in the development and homeostasis of multicellular organisms. Apoptosis induction can occur via intracellular mechanisms, for example after intensive DNA damage, or via triggering of death receptors. Death receptors belong to the tumour necrosis factor (TNF) receptor superfamily. Amongst the death receptors, the TNF-related apoptosisinducing ligand (TRAIL) and its five receptors stand out due to its complexity and tumour-specific killing activity. TRAIL can bind two apoptosis-inducing receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), two additional cell-bound receptors incapable of transmitting an apoptotic signal, TRAIL-R3 (LIT, DcR1) and TRAIL-R4 (TRUNDD, DcR2), sometimes also called decoy receptors, and lastly, a soluble receptor called osteoprotegerin (OPG). TRAIL has been shown to induce apoptosis in cancer cells in vivo without causing toxicity. On the basis of these findings, specific activation of TRAIL-R1 and TRAILR2 is currently evaluated for tumour therapy in early clinical trials. Yet, primary tumours are mostly resistant to TRAIL-induced apoptosis. Interestingly however, chemo- and radiotherapy can sensitise primary tumour cells to TRAIL-induced apoptosis whereas normal cells remain resistant also to such combinations. To understand the molecular mechanisms of tumour-cell-specific sensitisation to TRAIL, genome-wide RNA interference (RNAi) was used in an unbiased approach with the aim to identify novel factors involved in TRAIL-induced apoptosis and its inhibition. By screening the TRAIL-sensitive human cervix carcinoma cell line HeLa novel modulators of TRAIL signalling were identified. The studies presented in this thesis focus on the identification and validation of factors that are required for TRAIL apoptosis signalling, the molecular characterisation and the determination of their biochemical mechanism of action.
Supervisor: Walczak, Henning Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral