Identifying and characterising downstream substrates of mTORC1

mTORC1 functions as a nutrient sensor within the cell. It integrates signalling inputs from growth factors, nutrients and amino acids to regulate key cellular processes involving growth, proliferation and development. Perturbed mTORC1 signalling is a feature of a variety of diseases including the hamartoma syndromes, various cancer types as well as both autoimmune and neurological diseases yet many downstream signalling effects remain uncharacterised. The central aim of this study was to characterise mTORC1 as a regulator of transcription. This has been carried out focusing upon the regulation of two transcription factors which are fundamental to the pathophysiology of the hamartoma disorders and many types of cancer HIF-1a and STAT3. I have shown evidence that mTORC1 is able to regulate HIF-1a on a translational level through phosphorylation of 4E-BP1.1 have also shown that mTORC1 is able to regulate the synthesis of HIF-1a mRNA to further augment its activity. I present evidence that HIF-1a is subject to mTORC1 independent regulation from the upstream regulator TSC2. Significantly, mTORC1 inhibitors were able to normalise HIF-1a elevation through TSC1/2 loss in the absence of TSC1 but not TSC2 in a cell line model for the disease Tuberous Sclerosis. Furthermore I have shown that mTORCI can directly phosphorylate STAT3 at Ser727, promoting its transcriptional activity. I have also shown direct functional link between STAT3 and HIF-1a. This study includes an analysis of the current knowledge regarding these two transcription factors and highlights the possibilities for targeting this signalling pathway in the treatment of disease