Platelet-Derived Growth Factor–Induced p42/44 Mitogen-Activated Protein Kinase Activation and Cellular Growth Is Mediated by Reactive Oxygen Species in the Absence of <i>TSC2</i>/Tuberin

Finlay, Geraldine A.; Thannickal, Victor J.; Fanburg, Barry L.; Kwiatkowski, David J.

doi:10.1158/0008-5472.can-05-1394

Cited by 24 publications

(23 citation statements)

References 45 publications

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“…AMPK is in turn regulated at least in part through the LKB1 tumor suppressor gene involved in Peutz Jaegher's Syndrome, another cancer predisposing hamartoma syndrome (10). Like ATM-deficient cells, TSC2-null cells exhibit defects in redox homeostasis (11)(12)(13).…”

mentioning

confidence: 99%

ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS

Alexander

Cai

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

640

562

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Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency is associated with elevated reactive oxygen species (ROS). ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer, underscoring the importance of cellular pathways involved in redox homeostasis. We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS. We show that in response to elevated ROS, ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy. Importantly, elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin, which also rescues lymphomagenesis in Atm -deficient mice. Our results identify a cytoplasmic pathway for ROS-induced ATM activation of TSC2 to regulate mTORC1 signaling and autophagy, identifying an integration node for the cellular damage response with key pathways involved in metabolism, protein synthesis, and cell survival.

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mentioning

confidence: 99%

ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS

Alexander

Cai

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

640

562

View full text Add to dashboard Cite

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“…Moreover, increased sensitivity of Tsc2 À/À cells relative to Tsc2 We have previously shown that the growth advantage conferred by the loss of tuberin in ELT-3 cells is most apparent under conditions of serum withdrawal (30) and that Tsc2 À/À ELT-3 cell growth is also estrogen responsive (24). Figure 1B shows that …”

Section: Atorvastatin Inhibits the Growth Of Tsc2mentioning

confidence: 88%

Selective Inhibition of Growth of Tuberous Sclerosis Complex 2–Null Cells by Atorvastatin Is Associated with Impaired Rheb and Rho GTPase Function and Reduced mTOR/S6 Kinase Activity

et al. 2007

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Inactivating mutations in the tuberous sclerosis complex 2 (TSC2) gene, which encodes tuberin, result in the development of TSC and lymphangioleiomyomatosis (LAM). The tumor suppressor effect of tuberin lies in its GTPase-activating protein activity toward Ras homologue enriched in brain (Rheb), a Ras GTPase superfamily member. The statins, 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, have pleiotropic effects which may involve interference with the isoprenylation of Ras and Rho GTPases. We show that atorvastatin selectively inhibits the proliferation of Tsc2 À/À mouse embryo fibroblasts and ELT-3 smooth muscle cells in response to serum and estrogen, and under serum-free conditions. The isoprenoids farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) significantly reverse atorvastatin-induced inhibition of Tsc2 À/À cell growth, suggesting that atorvastatin dually targets a farnesylated protein, such as Rheb, and a geranylgeranylated protein, such as Rho, both of which have elevated activity in Tsc2 À/À cells.Atorvastatin reduced Rheb isoprenylation, GTP loading, and membrane localization. Atorvastatin also inhibited the constitutive phosphorylation of mammalian target of rapamycin, S6 kinase, and S6 found in Tsc2 À/À cells in an FPP-reversible manner and attenuated the high levels of phosphorylated S6 in Tsc2-heterozygous mice. Atorvastatin, but not rapamycin, attenuated the increased levels of activated RhoA in Tsc2 À/À cells, and this was reversed by GGPP. These results suggest that atorvastatin may inhibit both rapamycin-sensitive and rapamycin-insensitive mechanisms of tuberin-null cell growth, likely via Rheb and Rho inhibition, respectively. Atorvastatin may have potential therapeutic benefit in TSC syndromes, including LAM. [Cancer Res 2007;67(20):9878-86]

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“…The response of TSC2 À/À MEFs to peroxide is somewhat puzzling, as basal ROS levels are significantly higher in TSC2 À/À cells, as a result of increased mitochondrial function (Finlay et al, 2005). Moreover, peroxide or arsenite treatment of JB6 cells (a mouse epidermal cell type) has been shown to lead to an increase in S6K and 4EBP1 activation (Bae et al, 1999;Huang et al, 2002;Jung et al, 2003).…”

Section: Rosmentioning

confidence: 99%

Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?

2006

Oncogene

348

309

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The mammalian target of rapamycin (mTOR) is a serine/ threonine kinase that controls many aspects of cellular physiology, including transcription, translation, cell size, cytoskeletal organization and autophagy. Recent advances in the mTOR signaling field have found that mTOR exists in two heteromeric complexes, mTORC1 and mTORC2. The activity of mTORC1 is regulated by the integration of many signals, including growth factors, insulin, nutrients, energy availability and cellular stressors such as hypoxia, osmotic stress, reactive oxygen species and viral infection. In this review we highlight recent advances in the mTOR signaling field that relate to how the two mTOR complexes are regulated, and we discuss stress conditions linked to the mTOR signaling network that have not been extensively covered in other reviews. Given the diversity of signals that have been shown to impinge on mTOR, we also speculate on other signaltransduction pathways that may be linked to mTOR in the future.

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Platelet-Derived Growth Factor–Induced p42/44 Mitogen-Activated Protein Kinase Activation and Cellular Growth Is Mediated by Reactive Oxygen Species in the Absence of TSC2/Tuberin

Cited by 24 publications

References 45 publications

ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS

ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS

Selective Inhibition of Growth of Tuberous Sclerosis Complex 2–Null Cells by Atorvastatin Is Associated with Impaired Rheb and Rho GTPase Function and Reduced mTOR/S6 Kinase Activity

Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?

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