Regulation of mTOR and Cell Growth in Response to Energy Stress by REDD1

Abstract

The tuberous sclerosis tumor suppressors TSC1 and TSC2 regulate the mTOR pathway to control translation and cell growth in response to nutrient and growth factor stimuli. We have recently identified the stress response REDD1 gene as a mediator of tuberous sclerosis complex (TSC)-dependent mTOR regulation by hypoxia. Here, we demonstrate that REDD1 inhibits mTOR function to control cell growth in response to energy stress. Endogenous REDD1 is induced following energy stress, and REDD1 ؊/؊ cells are highly defective in dephosphorylation of the key mTOR substrates S6K and 4E-BP1 following either ATP depletion or direct activation of the AMP-activated protein kinase (AMPK). REDD1 likely acts on the TSC1/2 complex, as regulation of mTOR substrate phosphorylation by REDD1 requires TSC2 and is blocked by overexpression of the TSC1/2 downstream target Rheb but is not blocked by inhibition of AMPK. Tetracycline-inducible expression of REDD1 triggers rapid dephosphorylation of S6K and 4E-BP1 and significantly decreases cellular size. Conversely, inhibition of endogenous REDD1 by short interfering RNA increases cell size in a rapamycinsensitive manner, and REDD1 ؊/؊ cells are defective in cell growth regulation following ATP depletion. These results define REDD1 as a critical transducer of the cellular response to energy depletion through the TSC-mTOR pathway.

Maternal Undernutrition Induces the Expression of Hypoxia-Related Genes in the Fetal Brain

“…Moreover, the microarray data show the increase in expression level of Ddit4. Incidentally, Ddit4 functions as a negative regulator of the mTOR pathway (Sofer et al 2005). The mechanism of simultaneous upregulation of Ddit4 and mTOR mRNAs in the fetal brain needs to be confirmed by further experiments.…”

Metabolic consideration of epiphyseal growth: Survival responses in a taxing environment

“…In addition to hypoxic induction, REDD-1 can be induced by either ATP depletion or direct activation of the AMP-activated protein kinase (AMPK). These studies have shown that REDD-1 is a critical transducer of the cellular response to energy depletion and hypoxia through the mTOR pathway (Fig 3) [27][28][29].…”

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

“…Recently, the phosphorylation on Ser1345 has been shown to prime TSC2 for additional phosphorylation by GSK3b, which may be required for full activation of TSC2 . As an alternative to AMPK-induced activation of the TSC1:TSC2 complex, hypoxia-induced metabolic stress causes increased transcription of REDD, which also results in TSC2 activation (Figure 3) (Sofer et al, 2005). In contrast to these stress-induced TSC1:TSC2 complex activation pathways, various growth factors and cytokines inhibit activation of the TSC1:TSC2 complex by inhibitory phosphorylation of TSC1 or TSC2 through PI3K/PKB (also known as AKT), ERK/RSK or IKKb signaling modules (Figure 3) (Hay and Sonenberg, 2004;Inoki et al, 2005;Bhaskar and Hay, 2007;Huang and Manning, 2008).…”