Use this URL to cite or link to this record in EThOS:
Title: Investigation of a role for the endosomal deubiquitylase USP8 in cancer cell survival pathways
Author: Howarth, Alice Emma Louise
ISNI:       0000 0004 6422 3967
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
Availability of Full Text:
Access from EThOS:
Access from Institution:
Ubiquitylation is a reversible post-translational modification regulated by a number of enzymes. E1 activating, E2 conjugating and E3 ligase enzymes facilitate the modification of proteins by adding the 8.5kDa protein, ubiquitin, to lysine residues. The presence of seven internal lysine residues within ubiquitin itself allows the construction of complex chains with different chainlinkages. This complexity means that ubiquitylation plays a role in a number of cellular events including protein degradation. This signal is reversed through the action of deubiquitylases (DUBs). One of the roles for ubiquitylation is the targeting of proteins for lysosomal degradation and DUBs are important for this function. USP8 is an endocytic deubiquitylase involved in the regulation of a number of cell surface proteins. USP8 is important for endosomal sorting and the trafficking of cargo for degradation by the lysosome of a number of substrates. More recently USP8 has been linked to the regulation of cell viability of some cancer cells with a purported link to the PI3K-AKT cell survival pathway. In this thesis I identify a role for USP8 in the survival of EGFR-mutant, gefitinib-resistant, non-small cell lung cancer cells. Depletion of USP8 induces apoptosis in these cells. I confirm a link with the PI3K-AKT signalling pathway evidenced by a synthetic lethal effect of inhibiting this pathway when combined with USP8 depletion. In addition I identify a novel link between USP8 and the NRF2-KEAP1 reactive oxygen species (ROS) management pathway. USP8 depletion decreases protein levels of the NRF2 inhibitor, KEAP1. USP8 depletion sensitises NSCLC cells to induction of ROS. I conclude that USP8 is a DUB involved in a number of pathways including cell survival.
Supervisor: Urbé, S. ; Clague, M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral