Activation of a metabolic gene regulatory network downstream of mTOR complex 1

SREBP-1 expression and/or activity are regulated by PI3K/Akt signaling through mTORC1 in hepatocytes, mouse embryonic fibroblasts and Drosophila.

“SREBP-1 expression and/or activity are regulated by PI3K/Akt signaling through mTORC1 in hepatocytes (61), mouse embryonic fibroblasts (62) and in Drosphila (63).”

mTORC1 activation of SREBP-1 is essential for regulating lipid and sterol biogenesis.

“Further, mTORC1 activation of SREBP-1 has been shown to be essential for regulating lipid and sterol biogenesis (62).”

Activation of mTOR can increase ribose synthesis via the oxidative pentose phosphate pathway and enhance flux through pyrimidine and purine synthesis pathways.

“Activation of mTOR can increase ribose synthesis via the oxidative pentose phosphate pathway (Duvel et al., 2010) and enhance flux through the pyrimidine and purine synthesis pathways (Ben-Sahra et al., 2013; Ben-Sahra et al., 2016; Robitaille et al., 2013), suggesting that targeting nucleotide metabolism in tumor contexts with mTOR hyperactivation may be more effective.”

Targeting nucleotide metabolism may be more effective in tumor contexts with mTOR hyperactivation.

“Activation of mTOR can increase ribose synthesis via the oxidative pentose phosphate pathway (Duvel et al., 2010) and enhance flux through the pyrimidine and purine synthesis pathways (Ben-Sahra et al., 2013; Ben-Sahra et al., 2016; Robitaille et al., 2013), suggesting that targeting nucleotide metabolism in tumor contexts with mTOR hyperactivation may be more effective.”

mTORC1 facilitates cellular growth by a shift in glucose metabolism from OXPHOS to glycolysis, likely through an mTORC1-mediated increase in the translation of HIF1α and an increased flux through the PPP, which uses carbons from glucose to generate NADPH and other intermediary metabolites needed for proliferation and growth.

“mTORC1 facilitates cellular growth by a shift in glucose metabolism from OXPHOS to glycolysis, likely through an mTORC1-mediated increase in the translation of the transcription factor HIF1α and an increased flux through the PPP, which uses carbons from glucose to generate NADPH and other intermediary metabolites needed for proliferation and growth (276).”

Both mTOR complexes promote the transcription of genes involved in carbohydrate metabolism and lipogenesis, enhance protein translation by activating S6K, and downregulate catabolic processes through inhibiting FoxO and autophagy.

“Both complexes promote the transcription of genes involved in carbohydrate metabolism and lipogenesis, enhance protein translation by activating ribosomal protein 6 kinase (S6K) and, at the same time, downregulate catabolic processes through inhibiting the transcriptional activity of the forkhead box transcription factors family (FoxO) and autophagy”

Both mTOR complexes promote transcription of genes involved in carbohydrate metabolism and lipogenesis, enhance protein translation by activating S6K, and downregulate catabolic processes through inhibiting FoxO and autophagy.

“Both complexes promote the transcription of genes involved in carbohydrate metabolism and lipogenesis, enhance protein translation by activating ribosomal protein 6 kinase (S6K) and, at the same time, downregulate catabolic processes through inhibiting the transcriptional activity of the forkhead box transcription factors family (FoxO) and autophagy (Duvel et al., 2010; Wullschleger et al., 2006).”

SREBP-mediated de novo lipogenesis is a critical component of mTORC1-driven proliferation.

“Finally, a study isolating the cell-intrinsic consequences of mTORC1 activation demonstrated that SREBP-mediated de novo lipogenesis is a critical component of mTORC1-driven proliferation (Duvel et al., 2010).”