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1.
Protein synthesis and autophagic degradation are regulated in an opposite manner by mammalian target of rapamycin (mTOR), whereas under certain conditions it would be beneficial if they occurred in unison to handle rapid protein turnover. We observed a distinct cellular compartment at the trans side of the Golgi apparatus, the TOR-autophagy spatial coupling compartment (TASCC), where (auto)lysosomes and mTOR accumulated during Ras-induced senescence. mTOR recruitment to the TASCC was amino acid- and Rag guanosine triphosphatase-dependent, and disruption of mTOR localization to the TASCC suppressed interleukin-6/8 synthesis. TASCC formation was observed during macrophage differentiation and in glomerular podocytes; both displayed increased protein secretion. The spatial coupling of cells' catabolic and anabolic machinery could augment their respective functions and facilitate the mass synthesis of secretory proteins.  相似文献   

2.
肌肉细胞蛋白质合成能力与畜禽产肉量性状有关,试验旨在探究转录因子AT富集区4B(AT-rich interaction domain 4B,ARID4B)对牛磺酸(Taurine,Tau)调节成肌细胞C2C12蛋白质合成的影响.向体外培养C2C12细胞培养液中分别添加0、60、120、180和240μmol·L-1 T...  相似文献   

3.
To detect the mammalian target of rapamycin (mTOR) expressed in Cashmere goat fetal fibroblasts (GFb), mTOR gene was cloned from Inner Mongolia Cashmere goat (Capra hircus) and expressed in Escherichia coli followed by immunizing mice with the purified recombinant protein as an immunogen to produce the anti-goat mTOR recombinant polyclonal antibody. Antiserum was collected from the immunized mice after the fifth immunization and its titer was determined with enzyme-linked immunosorbent assay (ELISA). The results showed that the recombinant polyclonal antibody had a titer 1:200 000 and could react with the mTOR expressed in GFb cells with a specific and sensitive affinity. Western blot showed that mTOR expression and phospho-mTOR (Ser 2448) activity were inhibited when GFb cells were treated with CCI-779, an mTOR specific inhibitor.  相似文献   

4.
The enzyme mTOR (mammalian target of rapamycin) is a major target for therapeutic intervention to treat many human diseases, including cancer, but very little is known about the processes that control levels of mTOR protein. Here, we show that mTOR is targeted for ubiquitination and consequent degradation by binding to the tumor suppressor protein FBXW7. Human breast cancer cell lines and primary tumors showed a reciprocal relation between loss of FBXW7 and deletion or mutation of PTEN (phosphatase and tensin homolog), which also activates mTOR. Tumor cell lines harboring deletions or mutations in FBXW7 are particularly sensitive to rapamycin treatment, which suggests that loss of FBXW7 may be a biomarker for human cancers susceptible to treatment with inhibitors of the mTOR pathway.  相似文献   

5.
Regulation of dendritic protein synthesis by miniature synaptic events   总被引：2，自引：0，他引：2  
We examined dendritic protein synthesis after a prolonged blockade of action potentials alone and after a blockade of both action potentials and miniature excitatory synaptic events (minis). Relative to controls, dendrites exposed to a prolonged blockade of action potentials showed diminished protein synthesis. Dendrites in which both action potentials and minis were blocked showed enhanced protein synthesis, suggesting that minis inhibit dendritic translation. When minis were acutely blocked or stimulated, an immediate increase or decrease, respectively, in dendritic translation was observed. Taken together, these results reveal a role for miniature synaptic events in the acute regulation of dendritic protein synthesis in neurons.  相似文献   

6.
The failure of axons to regenerate is a major obstacle for functional recovery after central nervous system (CNS) injury. Removing extracellular inhibitory molecules results in limited axon regeneration in vivo. To test for the role of intrinsic impediments to axon regrowth, we analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. Deletion of PTEN (phosphatase and tensin homolog), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, in adult retinal ganglion cells (RGCs) promotes robust axon regeneration after optic nerve injury. In wild-type adult mice, the mTOR activity was suppressed and new protein synthesis was impaired in axotomized RGCs, which may contribute to the regeneration failure. Reactivating this pathway by conditional knockout of tuberous sclerosis complex 1, another negative regulator of the mTOR pathway, also leads to axon regeneration. Thus, our results suggest the manipulation of intrinsic growth control pathways as a therapeutic approach to promote axon regeneration after CNS injury.  相似文献   

7.
The evolutionarily conserved serine-threonine kinase mammalian target of rapamycin (mTOR) plays a critical role in regulating many pathophysiological processes. Functional characterization of the mTOR signaling pathways, however, has been hampered by the paucity of known substrates. We used large-scale quantitative phosphoproteomics experiments to define the signaling networks downstream of mTORC1 and mTORC2. Characterization of one mTORC1 substrate, the growth factor receptor-bound protein 10 (Grb10), showed that mTORC1-mediated phosphorylation stabilized Grb10, leading to feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated, mitogen-activated protein kinase (ERK-MAPK) pathways. Grb10 expression is frequently down-regulated in various cancers, and loss of Grb10 and loss of the well-established tumor suppressor phosphatase PTEN appear to be mutually exclusive events, suggesting that Grb10 might be a tumor suppressor regulated by mTORC1.  相似文献   

8.
The mammalian target of rapamycin (mTOR) protein kinase is a master growth promoter that nucleates two complexes, mTORC1 and mTORC2. Despite the diverse processes controlled by mTOR, few substrates are known. We defined the mTOR-regulated phosphoproteome by quantitative mass spectrometry and characterized the primary sequence motif specificity of mTOR using positional scanning peptide libraries. We found that the phosphorylation response to insulin is largely mTOR dependent and that mTOR exhibits a unique preference for proline, hydrophobic, and aromatic residues at the +1 position. The adaptor protein Grb10 was identified as an mTORC1 substrate that mediates the inhibition of phosphoinositide 3-kinase typical of cells lacking tuberous sclerosis complex 2 (TSC2), a tumor suppressor and negative regulator of mTORC1. Our work clarifies how mTORC1 inhibits growth factor signaling and opens new areas of investigation in mTOR biology.  相似文献   

9.
Bai X  Ma D  Liu A  Shen X  Wang QJ  Liu Y  Jiang Y 《Science (New York, N.Y.)》2007,318(5852):977-980
The mammalian target of rapamycin, mTOR, is a central regulator of cell growth. Its activity is regulated by Rheb, a Ras-like small guanosine triphosphatase (GTPase), in response to growth factor stimulation and nutrient availability. We show that Rheb regulates mTOR through FKBP38, a member of the FK506-binding protein (FKBP) family that is structurally related to FKBP12. FKBP38 binds to mTOR and inhibits its activity in a manner similar to that of the FKBP12-rapamycin complex. Rheb interacts directly with FKBP38 and prevents its association with mTOR in a guanosine 5'-triphosphate (GTP)-dependent manner. Our findings suggest that FKBP38 is an endogenous inhibitor of mTOR, whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability.  相似文献   

10.
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex   总被引：2，自引：0，他引：2  
Deregulation of Akt/protein kinase B (PKB) is implicated in the pathogenesis of cancer and diabetes. Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. We show that in Drosophila and human cells the target of rapamycin (TOR) kinase and its associated protein rictor are necessary for Ser473 phosphorylation and that a reduction in rictor or mammalian TOR (mTOR) expression inhibited an Akt/PKB effector. The rictor-mTOR complex directly phosphorylated Akt/PKB on Ser473 in vitro and facilitated Thr308 phosphorylation by PDK1. Rictor-mTOR may serve as a drug target in tumors that have lost the expression of PTEN, a tumor suppressor that opposes Akt/PKB activation.  相似文献   

11.
A hippocampal pyramidal neuron receives more than 10(4) excitatory glutamatergic synapses. Many of these synapses contain the molecular machinery for messenger RNA translation, suggesting that the protein complement (and thus function) of each synapse can be regulated on the basis of activity. Here, local postsynaptic protein synthesis, triggered by synaptic activation of metabotropic glutamate receptors, was found to modify synaptic transmission within minutes.  相似文献   

12.
FLCN基因参与多种代谢途径和细胞过程,国内外关于FLCN在奶牛乳腺发育过程中表达及调节的研究鲜有报道。应用RNA干扰技术和质粒转染技术改变FLCN基因在奶牛乳腺上皮细胞中表达量,流式细胞仪检测细胞增殖,采用qRT-PCR和Western blot检测FLCN对泌乳相关功能基因AMPK、mTOR、CyclinD1、Caspase3和β-酪蛋白表达的影响。结果表明,FLCN正向调节mTOR磷酸化水平,促进乳蛋白合成和细胞增殖,抑制细胞凋亡,负调控能量代谢调节子AMPK。FLCN在奶牛乳腺上皮细胞中可通过mTOR信号通路调控细胞增殖及乳蛋白合成,研究对揭示FLCN调控奶牛乳腺上皮细胞增殖和泌乳具有重要作用。  相似文献   

13.
The mammalian target of rapamycin （mTOR） signaling pathway is evolutionarily conserved, mTOR can integrate and converge a wide range of signals, including intracellular and extracellular nutrients, growth factors, energy and stress conditions, and has a crucial role in the vertebrate growth control. This review analyzed the main components and regulated factors of TOR signaling pathway, explained functions and mechanisms of roTOR during the individual growth, the development and its dynamic role, revealed its additional functions beyond the cell growth control, and finally reviewed the tissue specificity and time specificity of mTOR signaling pathway, and its regulation on sexual differentiation, tissue differentiation and organogenesis in the individual development.  相似文献   

14.
Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.  相似文献   

15.
Communication between neurons in the brain occurs primarily through synapses made onto elaborate treelike structures called dendrites. New electrical and optical recording techniques have led to tremendous advances in our understanding of how dendrites contribute to neuronal computation in the mammalian brain. The varied morphology and electrical and chemical properties of dendrites enable a spectrum of local and long-range signaling, defining the input-output relationship of neurons and the rules for induction of synaptic plasticity. In this way, diversity in dendritic signaling allows individual neurons to carry out specialized functions within their respective networks.  相似文献   

16.
The activation of metabotropic glutamate receptors (mGluRs) leads to long-term depression (mGluR-LTD) at many synapses of the brain. The induction of mGluR-LTD is well characterized, whereas the mechanisms underlying its expression remain largely elusive. mGluR-LTD in the ventral tegmental area (VTA) efficiently reverses cocaine-induced strengthening of excitatory inputs onto dopamine neurons. We show that mGluR-LTD is expressed by an exchange of GluR2-lacking AMPA receptors for GluR2-containing receptors with a lower single-channel conductance. The synaptic insertion of GluR2 depends on de novo protein synthesis via rapid messenger RNA translation of GluR2. Regulated synthesis of GluR2 in the VTA is therefore required to reverse cocaine-induced synaptic plasticity.  相似文献   

17.
Neuroscience research is shedding light on how neurons delegate their protein synthesis, shipping some messenger RNAs out to the dendrites, where they are translated to protein under the control of local synapses. Indeed, it appears that finely controlled, decentralized protein production may contribute to learning and memory in a way that neuroscientists could scarcely have imagined 20 years ago. As researchers presss on, they are filling in a picture of a complex loop of communication and supply, with synapses acting as local managers wielding more power than anyone might have imagined, to get what they need for carrying out the critical task of storing memories.  相似文献   

18.
Spatially resolved measurements of intracellular free calcium and of the changes produced by excitatory amino acids were made in neurons isolated from adult mammalian brain. Extremely long-lasting (minutes) Ca2+ gradients were induced in the apical dendrites of hippocampal CA1 neurons after brief (1 to 3 seconds), local application of either glutamate or N-methyl-D-aspartate (NMDA). These gradients reflect the continuous flux of Ca2+ into the dendrite. The sustained gradients, but not the immediate transient response to the agonists, were prevented by prior treatment with the protein kinase C inhibitor sphingosine. Expression of the long-lasting Ca2+ gradients generally required a priming or conditioning stimulus with the excitatory agonist. The findings demonstrate a coupling between NMDA receptor activation and long-lasting intracellular Ca2+ elevation that could contribute to certain use-dependent modifications of synaptic responses in hippocampal CA1 neurons.  相似文献   

19.
Synaptic inputs on dendrites are nonlinearly converted to action potential outputs, yet the spatiotemporal patterns of dendritic activation remain to be elucidated at single-synapse resolution. In rodents, we optically imaged synaptic activities from hundreds of dendritic spines in hippocampal and neocortical pyramidal neurons ex vivo and in vivo. Adjacent spines were frequently synchronized in spontaneously active networks, thereby forming dendritic foci that received locally convergent inputs from presynaptic cell assemblies. This precise subcellular geometry manifested itself during N-methyl-D-aspartate receptor-dependent circuit remodeling. Thus, clustered synaptic plasticity is innately programmed to compartmentalize correlated inputs along dendrites and may reify nonlinear synaptic integration.  相似文献   

20.
This study investigated cold plasmas for multiple biological applications. Our previous work has found dielectric barrier discharge plasma improves chicken sperm quality. The number of Sertoli cells (SCs) decides spermatogenesis. However, whether cold plasma can regulate SC proliferation remains unclear. This study explored the effects of cold plasma on immature chicken SC proliferation and the regulation mechanism. Results showed that cold plasma exposure at 2.4 W for 30 s twice with an interval of 6 h produced (P<0.05) the maximum SC viability, cell growth, and cell cycle progression. SC proliferation-promoting effect of cold plasma treatment was regulated by increasing (P<0.05) the adenosine triphosphate production and the respiratory enzyme activity in the mitochondria. This process was potentially mediated by the adenosine monophosphate-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR) signaling pathway, which was regulated by the microRNA (miRNA) targeting regulation directly and by the intracellular reactive oxygen species homeostasis indirectly. The cold plasma treatment increased (P<0.01) the miR-7450-5p expression and led to a decreased (P<0.01) AMPKα1 level. On the other hand, miR-100-5p expression was reduced (P<0.05) and led to an increased (P<0.05) mTOR level in SCs. A single-stranded synthetic miR-7450-5p antagomir and a double-stranded synthetic miR-100-5p agomir reduced (P<0.05) the SC proliferation. However, this could be ameliorated (P<0.05) by the cold plasma treatment. Our findings suggest that appropriate cold plasma treatment provides a safe strategy to improve SC proliferation, which is beneficial to elevating male chicken reproductive capacity.  相似文献   

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