Sterol regulatory element binding proteins: their role in the hypoxic response of cancer cells and their regulation by the Akt/mTORC1 pathway.
Doctoral thesis, UCL (University College London).
Sterol regulatory element binding proteins (SREBPs) are transcription factors that regulate the expression of genes involved in fatty acid and cholesterol biosynthesis. It has been established that SREBPs are regulated downstream of the PI3-Kinase/Akt/ mTORC1 signalling axis, a pathway that is frequently hyper-activated in cancer. SREBP target genes are upregulated in some forms of human cancer and a role for lipid metabolism in tumourigenesis has been suggested. Glioblastoma multiforme (GBM) is a cancer type that is associated with hyperactivation of the PI3-kinase/Akt signalling pathway and frequently displays poorly oxygenated (hypoxic) regions. SREBP1 has been implicated in the tumourigenic potential of this cancer type. However, the exact role of SREBPs in tumourigenesis is not known. In oder to investigate the SREBP-transcriptional response in cancer cells, a gene expression microarry analysis was carried out. It was found that SREBPs regulate genes involved in a variety of cellular processes including lipid metabolism, cell cycle regulation, redox regulation and cellular stress response. In addition, the role of SREBPs in lipid metabolism in hypoxia was investigated. It was found that hypoxia leads to distinct changes in the expression of different SREBP isoforms and their target genes and is associated with a decrease in pyruvate-dependent lipid synthesis and increased lipid storage. SREBPs are regulated downstream of the Akt/mTORC1 pathway, although the exact mechanism of this regulation remains to be elucidated. Possible mechanisms by which Akt and mTORC1 regulate SREBPs were investigated. It was found that inhibition of mTORC1 differentially affects the expression of individual SREBP isoforms. The results described in this thesis also show that mTORC1 modulates the transcriptional activity of mature SREBP and may regulate its stability in a GSK3-independent manner.
|Title:||Sterol regulatory element binding proteins: their role in the hypoxic response of cancer cells and their regulation by the Akt/mTORC1 pathway|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences|
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