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Title: Functional analysis and pharmacological targeting of the autophagy-regulating protein kinase, ULK1, in cancer
Author: Rozycka, E.
ISNI:       0000 0004 5915 9059
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2014
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Autophagy is an evolutionarily conserved catabolic process activated by various cellular stresses. In response to stress, cells degrade their cytoplasmic contents, macromolecules and organelles to generate amino acids, free fatty acids and ATP, providing building blocks for critical biosynthetic pathways. Thus, autophagy promotes the survival of cells by generating a nutrient pool and removing damaged cellular components. Consequently, deregulated autophagy has been implicated in many human pathologies, including cancer. The role of Unc51 -Like Kinase 1 and 2 (ULK1 and ULK2) in regulating cancer cell autophagy in response to nutrient deprivation was investigated. ULK1 and ULK2 silencing promoted cell type specific morphologic and molecular alterations in cancer cells from multiple origins that lead to inhibition of cell growth, cellular senescence and apoptotic cell death. At the molecular level, these affects were concomitant with impaired autophagy activity. Over-expression of ULK1 led to the identification of a novel phosphorylation event on Beclin1, a component of the hVps34 complex, essential for autophagosome formation. ULK1 phosphorylated Beclin1 at Ser30 in cells over-expressing active ULK1, or following nutrient deprivation. Further analysis revealed that ULK1 -dependent Ser30 phosphorylation of Beclin1 impairs the of ability of Beclin1/hVps34 to form complexes with UVRAG and Atg14L. Finally, the identification of a novel small molecule inhibitor of ULK1 (iULK1) is described that inhibits autophagosome formation. The iULK1 also exhibited semi-selective inhibition of receptor tyrosine kinase signalling and inhibited mTORC1 signalling in intact cells. Combined inhibition of ULK1 and mTORC1 signalling induced cell death in transformed cells and to a lesser extent in immortalised counterparts. Taken together, the data presented herein describe novel aspects of ULK biology, new mechanisms of ULK1 -dependent autophagy regulation and the validation of a small molecule inhibitor of the autophagy pathway that shows potential as a new class of cancer therapeutic.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available