Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor(s)

Dr. John Di Guglielmo

Abstract

Transforming growth factor beta (TGFβ) is a cytokine that regulates cellular adhesion, proliferation and apoptosis. In the context of cancer, TGFβ induces processes such as epithelial-to-mesenchymal transition (EMT). More recently, TGFβ has been discovered to also induce autophagy, and the relationship between TGFβ-induced EMT and autophagy remains unknown. Due to its involvement in autophagy and its established interactions with key TGFβ signaling proteins, this thesis focuses on the sequestosome 1 (p62/SQSTM1) protein. Here, I have shown that p62/SQSTM1 co-localizes with TGFβ receptors at the same time point that the receptors localize to Rab7-positive late endosomes. siRNA-mediated silencing of p62/SQSTM1 was also observed to prime non-small cell lung cancer cells to undergo an E-cadherin to N-cadherin shift, but this is not due to alterations of canonical TGFβ signaling. Furthermore, TGFβ induces a loss in nuclear p62 protein levels and sustained TGFβ incubation reduces total p62 levels, while converting light chain 3 beta (LC3B) I to LC3BII (a process that is a marker of autophagy). Finally, TGFβ-induced EMT and autophagy was shown to be dependent on the presence of the p62/SQSTM1-interacting proteins, TRAF6 and aPKC. Taken together, these findings provide new insight into the role of p62 in TGFβ signaling and autophagy, as well as provide possible relationships between EMT and autophagic processes.

Available for download on Saturday, June 29, 2019


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