Porstmann, Thomas;
(2008)
Regulation of sterol regulatory element binding protein (SREBP) by the PI3-kinase/Akt pathway and its role in the regulation of cell growth.
Doctoral thesis , UCL (University College London).
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Abstract
Protein kinase B (PKB/Akt) is a central component of intracellular signaling pathways. It becomes activated downstream of growth factor receptors and has been implicated in cell growth, proliferation and protection from apoptosis. Akt is also a mediator of metabolic insulin action, and stimulates glucose uptake, glycogen synthesis and lipogenesis. Activation of Akt resulted in induction of expression of several enzymes involved in cholesterol and fatty acid biosynthesis. These genes are transcriptional targets of the family of sterol regulatory element-binding proteins (SREBP). Induction of fatty acid synthase and HMG-CoA synthase, two key enzymes of the sterol and fatty acid biosynthesis pathway, by Akt requires SREBP. In addition, activation of Akt results in rapid accumulation of mature SREBP 1 in the nucleus. This process was independent of activation of glycogen synthase kinase 3 (GSK3) but required active complex 1 of the mammalian target of rapamycin (mTOR/TORCl). Analysis of cellular metabolites by NMR revealed that induction of glucose and amino acid uptake, lactate production as well as fatty acid and phosphoglyceride biosynthesis by Akt also requires TORC1 activity. Thus it can be postulated that induction of expression of lipogenic genes through activation of SREBP is part of an anabolic response to activation of the PI3K/Akt/mTOR pathway and may be required for the induction of lipid biosynthesis during cell growth and proliferation. The PI3K/Akt pathway has been implicated in regulation of cell and organ size in Drosophila melanogaster. Several transgenic fly lines carrying an RNAi construct targeting dSREBP expression were generated. Silencing of dSREBP resulted in a significant developmental delay as well as a profound loss of viability. Tissue specific silencing of dSREBP in the wing resulted in a reduction in cell and organ size suggesting that activation of dSREBP by the PI3K/Akt pathway could be involved in cell growth control in flies.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Regulation of sterol regulatory element binding protein (SREBP) by the PI3-kinase/Akt pathway and its role in the regulation of cell growth |
| Identifier: | PQ ETD:592560 |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| UCL classification: | |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1445240 |
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