Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis

Lacher, Markus D.; Pincheira, Roxana; Zhu, Zhou; Camoretti-Mercado, Blanca; Matli, Mary; Warren, Robert S.; Castro, Ariel F.

doi:10.1038/onc.2010.393

Cited by 42 publications

(54 citation statements)

References 51 publications

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“…Of note, the model chosen in our investigations considered that most studies on mTOR have been performed in animals deficient in mTOR-related molecules (i.e., Rheb, Tsc1/Tsc2, mLST8, raptor, rictor) (36)(37)(38). Although these models have proven very valuable for the comprehension of key mechanisms of molecular action of related factors, we elected to study, in a relatively more physiological system, the leptin-mTOR axis, because the ablation of selected genes might cause compensatory activities and, more importantly, could not address the dynamic and oscillatory changes that we wanted to investigate in Teffs.…”

Section: Discussionmentioning

confidence: 99%

Leptin-Induced mTOR Activation Defines a Specific Molecular and Transcriptional Signature Controlling CD4+ Effector T Cell Responses

Procaccini

Rosa

Galgani

et al. 2012

The Journal of Immunology

121

110

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The sensing by T cells of metabolic and energetic changes in the microenvironment can determine the differentiation, maturation, and activation of these cells. Although it is known that mammalian target of rapamycin (mTOR) gauges nutritonal and energetic signals in the extracellular milieu, it is not known how mTOR and metabolism influence CD4+CD25−FOXP3− effector T cell (Teff) responses. In this article, we show that leptin-induced activation of mTOR, which, in turn, controls leptin production and signaling, causes a defined cellular, biochemical, and transcriptional signature that determine the outcome of Teff responses, both in vitro and in vivo. The blockade of leptin/leptin receptor signaling, induced by genetic means or by starvation, leads to impaired mTOR activity that inhibits the proliferation of Teffs in vivo. Notably, the transcriptional signature of Teffs in the presence of leptin blockade appears similar to that observed in rapamycin-treated Teffs. These results identify a novel link between nutritional status and Teff responses through the leptin–mTOR axis and define a potential target for Teff modulation in normal and pathologic conditions.

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Section: Discussionmentioning

confidence: 99%

Leptin-Induced mTOR Activation Defines a Specific Molecular and Transcriptional Signature Controlling CD4+ Effector T Cell Responses

Procaccini

Rosa

Galgani

et al. 2012

The Journal of Immunology

121

110

View full text Add to dashboard Cite

show abstract

“…Lacher et al . [70] reported that Rheb activates AMPK and reduces the level of p27Kip1 in Tsc2 -null cells and that these effects occur independent of mTORC1 activation. Involvement of Rheb in the regulation of B-Raf kinase activity was suggested from overexpression studies [71], [72].…”

Section: Mtorc1-dependent and Independent Functions Of Rhebmentioning

confidence: 99%

Recent progress in the study of the Rheb family GTPases

Heard

Fong

Bathaie

et al. 2014

Cellular Signalling

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In this review we highlight recent progress in the study of Rheb family GTPases. Structural studies using X-ray crystallography and NMR have given us insight into unique features of this GTPase. Combined with mutagenesis studies, these works have expanded our understanding of residues that affect Rheb GTP/GDP bound ratios, effector protein interactions, and stimulation of mTORC1 signaling. Analysis of cancer genome databases has revealed that several human carcinomas contain activating mutations of the protein. Rheb’s role in activating mTORC1 signaling at the lysosome in response to stimuli has been further elucidated. Rheb has also been suggested to play roles in other cellular pathways including mitophagy and peroxisomal ROS response. A number of studies in mice have demonstrated the importance of Rheb in development, as well as in a variety of functions including cardiac protection and myelination. We conclude with a discussion of future prospects in the study of Rheb family GTPases.

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“…AMPK is activated under low glucose conditions and plays a key role in the adaptive response to nutrient stress by limiting anabolism and promoting catabolism. AMPK is hyperactivated in TSC2 −/− MEFs ((36, 37) and data not shown). The AMPK inhibitor compound C (38) did not diminish 4F2hc up-regulation under nutrient stress in TSC2 +/+ or TSC2 −/− MEFs (Fig.…”

Section: Resultsmentioning

confidence: 85%

Loss of TSC2 confers resistance to ceramide and nutrient deprivation

et al. 2013

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Nutrient stress that produces quiescence and catabolism in normal cells is lethal to cancer cells because oncogenic mutations constitutively drive anabolism. One driver of biosynthesis in cancer cells is the mTORC1 signaling complex. Activating mTORC1 by deleting its negative regulator TSC2 leads to hypersensitivity to glucose deprivation. We have previously shown that ceramide kills cells in part by triggering nutrient transporter loss and restricting access to extracellular amino acids and glucose suggesting that TSC2-deficient cells would be hypersensitive to ceramide. However, murine embryonic fibroblasts (MEFs) lacking TSC2 were highly resistant to ceramide-induced death. Consistent with the observation that ceramide limits access to both amino acids and glucose, TSC2−/− MEFs also had a survival advantage when extracellular amino acids and glucose were both reduced. As TSC2−/− MEFs were resistant to nutrient stress despite sustained mTORC1 activity, we assessed whether mTORC1 signaling might be beneficial under these conditions. In low amino acid and glucose medium and following ceramide-induced nutrient transporter loss, elevated mTORC1 activity significantly enhanced the adaptive up-regulation of new transporter proteins for amino acids and glucose. Strikingly, the introduction of oncogenic Ras abrogated the survival advantage of TSC2−/− MEFs upon ceramide treatment most likely by increasing nutrient demand. These results suggest that, in the absence of oncogene-driven biosynthetic demand, mTORC1 dependent translation facilitates the adaptive cellular response to nutrient stress.

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Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis

Cited by 42 publications

References 51 publications

Leptin-Induced mTOR Activation Defines a Specific Molecular and Transcriptional Signature Controlling CD4+ Effector T Cell Responses

Leptin-Induced mTOR Activation Defines a Specific Molecular and Transcriptional Signature Controlling CD4+ Effector T Cell Responses

Recent progress in the study of the Rheb family GTPases

Loss of TSC2 confers resistance to ceramide and nutrient deprivation

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