Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and

Question

Stimulation of de novo pyrimidine synthesis by growth signaling

through mTOR and S6K1, Ben-Sahra ET AL, Science 2013

1.How does mTORC1 affect lipid and sterol synthesis?

2. How is mTORC1 activated?

3.What 5 metabolites decrease in response to treatment of cells with rapamycin?

4. What pathway had significant in metabolic flux in Tsc2 -/-cells?

5. Describe the data that shows the affect on Tsc-/- cells of long-term sensitivity to rapamycin by the formation of carbamoyl-aspartate. Explain how these findings were confirmed?

6. Explain the results showing that glutamine flux was not affected by rapamycin. From you knowledge of glutamine synthesis and utilization, what is the reason for it not might not being controlled in these transformed cells? Hint think glutamine utilization as a source of KG.

7. Interpret the Insulin data. How does the analysis of the data in Fig. 4E, Fig. S7A, & Fig. S7D especially show about Insulin?

8. What does the CAD transcription and expression data show about the affect of mTORC1 on CAD?

9. Insulin stimulates the phosphorylation of CAD. Discuss the data and what does this show about control of this pathway?

10. Analyze the data of Figure 4. What do these results indicate?

Explanation / Answer

1) Mechanistic target of Rapamycin complex (mTORC1) is a protein kinase that senses the presence of nutrients and is involved in various cellular processes. mTORC1 is involved in protein synthesis, inhibiting autophagy and recently it's central role in lipid and sterol synthesis has been established.

In lipid metabolism, mTORC1 is involved in,

A small G protein called Rheb activates or inhibits mTORC1 activity by altering it's GTP binding status. GTPase activating protein complex comprises of TSC1, TSC2 and TBC1D7 also known as TSC - TBC complex.

SREBP (sterol regulatory element binding proteins) are transcriptional factors that bind to sterol regulatory element in DNA sequence. SREBP processing and activation is regulated by mTORC1 by S6K and lipid1. Stimulation of SREBP by mTORC1 leads to activation of many lipogenic enzyme genes involved in lipid and sterol synthesis.

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