Identification and functional analysis of novel components of the TRAIL apoptosis signalling pathway
Author(s)
Falschlehner, Christina
Type
Thesis
Abstract
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.
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.
Date Issued
2009
Date Awarded
2009-05
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Walczak, Henning
Creator
Falschlehner, Christina
Publisher Department
Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)