Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice ...deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced β-cell mass. However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced β-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. Moreover, wild-type mice on a high fat diet as well as K/K Ay and ob/ob (also known as Lep/Lep) micetwo genetic models of obesityhave markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.
Mammalian TOR: A Homeostatic ATP Sensor Dennis, Patrick B.; Jaeschke, Anja; Saitoh, Masao ...
Science (American Association for the Advancement of Science),
11/2001, Letnik:
294, Številka:
5544
Journal Article
Recenzirano
The bacterial macrolide rapamycin is an efficacious anticancer agent against solid tumors. In a hypoxic environment, the increase in mass of solid tumors is dependent on the recruitment of mitogens ...and nutrients. When nutrient concentrations change, particularly those of essential amino acids, the mammalian Target of Rapamycin (mTOR) functions in regulatory pathways that control ribosome biogenesis and cell growth. In bacteria, ribosome biogenesis is independently regulated by amino acids and adenosine triphosphate (ATP). Here we demonstrate that the mTOR pathway is influenced by the intracellular concentration of ATP, independent of the abundance of amino acids, and that mTOR itself is an ATP sensor.
The 44Ti-powered spectrum of SN 1987A Jerkstrand, A.; Fransson, C.; Kozma, C.
Astronomy and astrophysics (Berlin),
06/2011, Letnik:
530
Journal Article
Recenzirano
Odprti dostop
SN 1987A provides a unique opportunity to study the evolution of a supernova from explosion into very late phases. Owing to the rich chemical structure, the multitude of physical processes involved ...and extensive radiative transfer effects, detailed modeling is needed to interpret the emission from this and other supernovae. In this paper, we analyze the late-time (about eight years) Hubble Space Telescope spectrum of the SN 1987A ejecta, where 44Ti is the dominant power source. Based on an explosion model for a 19 M⊙ progenitor, we compute a model spectrum by calculating the degradation of positrons and gamma-rays from the radioactive decays, solving the equations governing temperature, ionization balance and NLTE level populations, and treating the radiative transfer with a Monte Carlo technique. We obtain a UV/optical/NIR model spectrum that reproduces most of the lines in the observed spectrum with good accuracy. We find non-local radiative transfer in atomic lines to be an important process also at this late stage of the supernova, with ~30% of the emerging flux in the optical and NIR coming from scattering/fluorescence. We investigate the question of where the positrons deposit their energy, and favor the scenario where they are locally trapped in the Fe/He clumps by a magnetic field. Energy deposition into these largely neutral Fe/He clumps makes Fe I lines prominent in the emerging spectrum. With the best available estimates for the dust extinction, we determine the amount of 44Ti produced in the explosion to be \hbox{$1.5_{-0.5}^{+0.5}\e{-4}\Mo$}1.5-0.5+0.5 × 10-4 M⊙.
Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In ...this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. We found that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with RAD001, a rapamycin derivative, showed an administration schedule-dependent increase in activation of the MAPK pathway. RAD001 treatment also led to MAPK activation in a mouse model of prostate cancer. We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway. Significantly, pharmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors, currently employed as single agents in the clinic, for the treatment of human cancers.
Hypothalamic mTOR Signaling Regulates Food Intake Cota, Daniela; Proulx, Karine; Smith, Kathi A. Blake ...
Science (American Association for the Advancement of Science),
05/2006, Letnik:
312, Številka:
5775
Journal Article
Recenzirano
The mammalian Target of Rapamycin (mTOR) protein is a serine-threonine kinase that regulates cell-cycle progression and growth by sensing changes in energy status. We demonstrated that mTOR signaling ...plays a role in the brain mechanisms that respond to nutrient availability, regulating energy balance. In the rat, mTOR signaling is controlled by energy status in specific regions of the hypothalamus and colocalizes with neuropeptide Y and proopiomelanocortin neurons in the arcuate nucleus. Central administration of leucine increases hypothalamic mTOR signaling and decreases food intake and body weight. The hormone leptin increases hypothalamic mTOR activity, and the inhibition of mTOR signaling blunts leptin's anorectic effect. Thus, mTOR is a cellular fuel sensor whose hypothalamic activity is directly tied to the regulation of energy intake.
Both the formation of long-term memory (LTM) and late-long-term potentiation (L-LTP), which is thought to represent the cellular model of learning and memory, require de novo protein synthesis. The ...mammalian target of Rapamycin (mTOR) complex I (mTORC1) integrates information from various synaptic inputs and its best characterized function is the regulation of translation. Although initial studies have shown that rapamycin reduces L-LTP and partially blocks LTM, recent genetic and pharmacological evidence indicating that mTORC1 promotes L-LTP and LTM is controversial. Thus, the role of mTORC1 in L-LTP and LTM is unclear. To selectively inhibit mTORC1 activity in the adult brain, we used a "pharmacogenetic" approach that relies on the synergistic action of a drug (rapamycin) and a genetic manipulation (mTOR heterozygotes, mTOR⁺/⁻ mice) on the same target (mTORC1). Although L-LTP and LTM are normal in mTOR⁺/⁻ mice, application of a low concentration of rapamycin--one that is subthreshold for WT mice--prevented L-LTP and LTM only in mTOR⁺/⁻ mice. Furthermore, we found that mTORC1-mediated translational control is required for memory reconsolidation. We provide here direct genetic evidence supporting the role of mTORC1 in L-LTP and behavioral memory.
Tumor suppressor genes evolved as negative effectors of mitogen and nutrient signaling pathways, such that mutations in these genes can lead to pathological states of growth. Tuberous sclerosis (TSC) ...is a potentially devastating disease associated with mutations in two tumor suppressor genes,
TSC1 and
2, that function as a complex to suppress signaling in the mTOR/S6K/4E-BP pathway. However, the inhibitory target of TSC1/2 and the mechanism by which it acts are unknown. Here we provide evidence that TSC1/2 is a GAP for the small GTPase Rheb and that insulin-mediated Rheb activation is PI3K dependent. Moreover, Rheb overexpression induces S6K1 phosphorylation and inhibits PKB phosphorylation, as do loss-of-function mutations in TSC1/2, but contrary to earlier reports Rheb has no effect on MAPK phosphorylation. Finally, coexpression of a human TSC2 cDNA harboring a disease-associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1.
Cells adapt to nutrient and energy deprivation by inducing autophagy, which is regulated by the mammalian target of rapamycin (mTOR) and AMP-activated protein kinases (AMPKs). We found that cell ...metabolism significantly influences the ability to induce autophagy, with mitochondrial complex I function being an important factor in the initiation, amplitude, and duration of the response. We show that phenformin or genetic defects in complex I suppressed autophagy induced by mTOR inhibitors, whereas autophagy was enhanced by strategies that increased mitochondrial metabolism. We report that mTOR inhibitors significantly increased select phospholipids and mitochondrial-associated membranes (MAMs) in a complex I-dependent manner. We attribute the complex I autophagy defect to the inability to increase MAMs, limiting phosphatidylserine decarboxylase (PISD) activity and mitochondrial phosphatidylethanolamine (mtPE), which support autophagy. Our data reveal the dynamic and metabolic regulation of autophagy.
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•Phenformin, metformin, and mitochondrial complex I defects suppress autophagy•Defects in glycolysis and OXPHOS have opposing effects on autophagy•Autophagy is enhanced by a metabolic shift toward OXPHOS•Mitochondrial-associated membranes and mitochondrial PE support autophagy
Autophagy is a survival response to starvation conditions, which inhibit the mTOR kinase. Thomas et al. demonstrate that autophagy induced by mTOR inhibitors is limited by phenformin and defects in OXPHOS but enhanced by strategies that increase mitochondrial energy and phospholipid metabolism. The therapeutic relevance of these findings is discussed.
Caloric restriction (CR) protects against aging and disease, but the mechanisms by which this affects mammalian life span are unclear. We show in mice that deletion of ribosomal S6 protein kinase 1 ...(S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity. Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. Our results demonstrate that S6K1 influences healthy mammalian life-span and suggest that therapeutic manipulation of S6K1 and AMPK might mimic CR and could provide broad protection against diseases of aging.
We present JEKYLL, a new code for modelling of supernova (SN) spectra and lightcurves based on Monte-Carlo (MC) techniques for the radiative transfer. The code assumes spherical symmetry, homologous ...expansion and steady state for the matter, but is otherwise capable of solving the time-dependent radiative transfer problem in non-local-thermodynamic-equilibrium (NLTE). The method used was introduced in a series of papers by Lucy, but the full time-dependent NLTE capabilities of it have never been tested. Here, we have extended the method to include non-thermal excitation and ionization as well as charge-transfer and two-photon processes. Based on earlier work, the non-thermal rates are calculated by solving the Spencer-Fano equation. Using a method previously developed for the SUMO code, macroscopic mixing of the material is taken into account in a statistical sense. To save computational power a diffusion solver is used in the inner region, where the radiation field may be assumed to be thermalized. In addition, a statistical Markov-chain model is used to sample the emission frequency more efficiently, and we introduce a method to control the sampling of the radiation field, which is used to reduce the noise in the radiation field estimators. Except for a description of JEKYLL, we provide comparisons with the ARTIS, SUMO and CMFGEN codes, which show good agreement in the calculated spectra as well as the state of the gas. In particular, the comparison with CMFGEN, which is similar in terms of physics but uses a different technique, shows that the Lucy method does indeed converge in the time-dependent NLTE case. Finally, as an example of the time-dependent NLTE capabilities of JEKYLL, we present a model of a Type IIb SN, taken from a set of models presented and discussed in detail in an accompanying paper. Based on this model we investigate the effects of NLTE, in particular those arising from non-thermal excitation and ionization, and find strong effects even on the bolometric lightcurve. This highlights the need for full NLTE calculations when simulating the spectra and lightcurves of SNe.
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