SREBP Activity Is Regulated by mTORC1 and Contributes to Akt-Dependent Cell Growth

Abstract

SummaryCell growth (accumulation of mass) needs to be coordinated with metabolic processes that are required for the synthesis of macromolecules. The PI3-kinase/Akt signaling pathway induces cell growth via activation of complex 1 of the target of rapamycin (TORC1). Here we show that Akt-dependent lipogenesis requires mTORC1 activity. Furthermore, nuclear accumulation of the mature form of the sterol responsive element binding protein (SREBP1) and expression of SREBP target genes was blocked by the mTORC1 inhibitor rapamycin. We also show that silencing of SREBP blocks Akt-dependent lipogenesis and attenuates the increase in cell size in response to Akt activation in vitro. Silencing of dSREBP in flies caused a reduction in cell and organ size and blocked the induction of cell growth by dPI3K. Our results suggest that the PI3K/Akt/TOR pathway regulates protein and lipid biosynthesis in an orchestrated manner and that both processes are required for cell growth.

Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

“…However, whether SREBPs activated additional genes that are more specifically related to phagocytosis or toxin response was not addressed. SREBP-1 has also been directly implicated in controlling cell size through AKT signaling that is at least partially dependent on the mTORC1 pathway (Porstmann et al 2008). Taken together, the lipid and nutrient regulation of SREBPs underscores their fundamental involvement in other physiologic responses broadly related to cell-environment interactions.…”

“…Insulin also activates protein kinase C l (PKCl), which has been associated with defective liver lipid metabolism through changes in SREBP-1c gene expression (Matsumoto et al 2003;Taniguchi et al 2006), and more recent studies indicate that PKCl activation of SREBP-1c is associated with obesity, diabetes, and hyperlipidemia in animal models (Sajan et al 2009a,b). The effects of AKT on SREBP-1 function are complex, as there appear to be both rapamycin-sensitive (mTORC1-dependent) and rapamycin-insensitive effects of AKT on the level of mature nuclear SREBP-1 protein (Porstmann et al 2008). One of the rapamycin-insensitive effects is likely through the direct action of AKT on SREBP-1 maturation.…”

Metabolic assessment of the action of targeted cancer therapeutics using magnetic resonance spectroscopy

“…Furthermore, enhanced lipid synthesis after Akt activation was reported and postulated to result from the acceleration of the de novo membrane synthesis required to produce increased cell volume (Porstmann et al, 2008). This effect was reversed by the inhibition of PI3K/Akt using LY294002 and wortmannin, both of which resulted in a decrease in the PC content detected by MRS (Beloueche-Babari et al, 2006).…”

Myelination and mTOR

“…mTORC1 promotes the processing of SREBPs to their mature forms. Subsequently, mature SREBPs induce the expression of several enzymes involved in fatty acid and cholesterol synthesis (Porstmann et al, 2008). Although the exact mechanisms are not yet defined, S6K1 has been implicated in this process (Düvel et al, 2010; Owen et al, 2012).…”