mTOR Complex1–S6K1 signaling: at the crossroads of obesity, diabetes and cancer

Dann, Stephen G.; Selvaraj, Anand; Thomas, George

doi:10.1016/j.molmed.2007.04.002

Cited by 429 publications

(370 citation statements)

References 86 publications

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“…S4). The same analogy can be drawn for mammalian kinases Akt1p and S6K1, also protooncogenes (36,37), and their yeast homologue Sch9p, which we recovered twice in our screen. In light of this and given the highly evolutionary conserved C-terminal domain of protein phosphatase 2A, it would be of great interest to see how the protein phosphatase methyltransferase affects cell signaling, in both yeast and human.…”

Section: Starving Yeast Auxotrophs and Human Tumor Cells May Waste Glsupporting

confidence: 62%

Influence of genotype and nutrition on survival and metabolism of starving yeast

Boer

Amini

Botstein

2008

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

124

183

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Starvation of yeast cultures limited by auxotrophic requirements results in glucose wasting and failure to achieve prompt cell-cycle arrest when compared with starvation for basic natural nutrients like phosphate or sulfate. We measured the survival of yeast auxotrophs upon starvation for different nutrients and found substantial differences: When deprived of leucine or uracil, viability declined exponentially with a half-life of <2 days, whereas when the same strains were deprived of phosphate or sulfate, the half-life was Ϸ10 days. The survival rates of nongrowing auxotrophs deprived of uracil or leucine depended on the carbon source available during starvation, but were independent of the carbon source during prior growth. We performed an enrichment procedure for mutants that suppress lethality during auxotrophy starvation. We repeatedly found loss-of-function mutations in a number of functionally related genes. Mutations in PPM1, which methylates protein phosphatase 2A, and target of rapamycin (TOR1) were characterized further. Deletion of PPM1 almost completely suppressed the rapid lethality and substantially suppressed glucose wasting during starvation for leucine or uracil. Suppression by a deletion of TOR1 was less complete. We suggest that, similar to the Warburg effect observed in tumor cells, starving yeast auxotrophs wastes glucose as a consequence of the failure of conserved growth control pathways. Furthermore, we suggest that our results on condition-dependent chronological lifespan have important implications for the interpretation and design of studies on chronological aging. auxotrophy starvation ͉ chronological aging ͉ Warburg effect

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Section: Starving Yeast Auxotrophs and Human Tumor Cells May Waste Glsupporting

confidence: 62%

Influence of genotype and nutrition on survival and metabolism of starving yeast

Boer

Amini

Botstein

2008

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

124

183

View full text Add to dashboard Cite

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“…11). The regulation of mTOR activity directs the cellular response to nutrient status, which is especially sensitive to the availability of amino acids (6,33). In vivo experiments of fasting and refeeding have recently shown the activation of Akt in the liver of refed mice, and experiments with liver-specific rictor knockout mice demonstrated mTORC2 dependence (34).…”

Section: Discussionmentioning

confidence: 99%

Akt-dependent Activation of the Heart 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase (PFKFB2) Isoenzyme by Amino Acids

Novellasdemunt

Tato

Navarro-Sabaté

et al. 2013

Journal of Biological Chemistry

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“…This effect also involves S6K1 in maintenance of glucose tolerance. S6K1 significantly supports the size of insulin-producing ␤ cells within pancreatic Langerhans islets (24,25). Thus, in S6K1 Ϫ/Ϫ mice, the insulin mass was diminished, which resulted in ineffective secretion of insulin upon glucose administration (21,23).…”

mentioning

confidence: 89%

The Death Effector Domain-containing DEDD Supports S6K1 Activity via Preventing Cdk1-dependent Inhibitory Phosphorylation

Kurabe

Arai

Nishijima

et al. 2009

Journal of Biological Chemistry

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؊/؊ cells and tissues. Consequently, as in S6K1 ؊/؊ mice, the insulin mass within pancreatic islets was reduced in DEDD ؊/؊ mice, resulting in glucose intolerance. These findings suggest a novel cell sizing mechanism achieved by DEDD through the maintenance of S6K1 activity prior to cell division. Our results also suggest that DEDD may harbor important roles in glucose homeostasis and that its deficiency might be involved in the pathogenesis of type 2 diabetes mellitus.Cell size is closely related to specialized cell function and to the specific patterning of tissues in the body. Cell sizing is regulated mainly by two mechanisms: cell cycle control and the biochemical response to nutrients and/or growth factors (1-5). During cell cycle progression, both the G 1 (which is believed to be dominant) and the G 2 periods are important for cells to increase their volume (6 -9). In addition, we recently provided evidence that the mitotic period (M phase) also influences cell size, through analysis of DEDD-deficient mice (10, 11). The DEDD molecule was initially described as a member of the death effector domain (DED) 2 -containing protein family (12). Although the absence of DEDD did not apparently influence progression of apoptosis (10), we found that during mitosis, DEDD is associated with Cdk1-cyclin B1 and that it decreases the kinase activity of Cdk1. This response impedes the Cdk1-dependent mitotic program to shut off synthesis of ribosomal RNA (rRNA) and protein and is consequently useful in gaining sufficient cell growth prior to cell division. Depletion of DEDD consistently results in a shortened mitotic duration and an overall reduction in the amount of cellular rRNA and protein and, furthermore, in cell and body size (10,11).Of the biochemical responses responsible for cell sizing, the signaling cascade involving phosphatydilinositol 3-kinase (PI3K) and its downstream target of rapamycin (TOR) is most crucial (13)(14)(15). In mammals, upon stimulation by growth factors, including insulin, the mammalian TOR (mTOR) cooperates with PI3K-dependent effectors to activate S6K1, thereby phosphorylating the 40 S ribosomal protein S6, and subsequently enhances translation of the 5Ј-terminal oligopyrimidine sequences that encode components of the translational machinery. This reaction increases the number of ribosomes and the efficacy of protein synthesis, thus critically promoting cell growth (16 -18). Therefore, mice deficient for S6K1 (S6K1 Ϫ/Ϫ ) had reduced cell and body size (19 -23). This effect also involves S6K1 in maintenance of glucose tolerance. S6K1 * This work was supported, in whole or in part, by National Institutes of Health Grant 5RO1AI50948-05. This work was also supported by grants-in-aid from the Ministry of Education, Sports, Culture, Science, and Technology, Japan, the Takeda Science Foundation (to T. M. and S. A.), the Mitsubishi Pharma Research Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Danone Institute of Nutrition for Health, the Uehara Memorial Fou...

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mTOR Complex1–S6K1 signaling: at the crossroads of obesity, diabetes and cancer

Cited by 429 publications

References 86 publications

Influence of genotype and nutrition on survival and metabolism of starving yeast

Influence of genotype and nutrition on survival and metabolism of starving yeast

Akt-dependent Activation of the Heart 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase (PFKFB2) Isoenzyme by Amino Acids

The Death Effector Domain-containing DEDD Supports S6K1 Activity via Preventing Cdk1-dependent Inhibitory Phosphorylation

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