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Eric Klann - One of the best experts on this subject based on the ideXlab platform.
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Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice
2020Co-Authors: Sameer Aryal, Francesco Longo, Eric KlannAbstract:Loss of the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP is widely thought to repress protein synthesis, but its translational targets and modes of control remain in dispute. We previously showed that genetic removal of p70 S6 Kinase 1 (S6K1) corrects altered protein synthesis as well as synaptic and behavioral phenotypes in FXS mice. In this study, we examined the gene-specificity of altered mRNA translation in FXS model mice and the mechanism of rescue with genetic reduction of S6K1 by carrying out ribosome profiling and RNA-Seq on cortical lysates from wild-type, FXS, S6K1 knockout, and double knockout mice. We observed reduced ribosome footprint abundance in the majority of differentially translated genes in the cortices of FXS mice. We used molecular assays to discover evidence that the reduction in ribosome footprint abundance reflects an increased rate of ribosome translocation, which is captured as a decrease in the number of translating ribosomes at steady state, and is normalized by inhibition of S6K1. We also found that genetic removal of S6K1 prevented a positive-to-negative gradation of alterations in translation efficiencies (RF/mRNA) with coding sequence length across mRNAs in FXS mouse cortices. Our findings reveal the identities of dysregulated mRNAs and a molecular mechanism by which reduction of S6K1 prevents altered translation in FXS.
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Interactions between sleep disruption, motor learning, and p70 S6 Kinase 1 signaling.
Sleep, 2019Co-Authors: Korey Kam, Mihwa Kang, C Yasemin Eren, Ward D Pettibone, Heather Bowling, Shantal Taveras, Rebecca K. Chen, Natasha V Berryman, Eric KlannAbstract:Offline gains in motor performance after initial motor learning likely depend on sleep, but the molecular mechanisms by which this occurs are understudied. Regulation of mRNA translation via p70 S6 Kinase 1 (S6K1) signaling represents one potential mechanism, as protein synthesis is thought to be increased during sleep compared to wake and is necessary for several forms of long-term memory. Using phosphorylation of ribosomal protein S6 (RpS6) as a readout of S6K1 activity, we demonstrate that a period of 10 h of acute sleep disruption impairs both S6K1 signaling and offline gains in motor performance on the rotarod in adult wild type C57/Bl6 mice. Rotarod motor learning results in increased abundance of RpS6 in the striatum, and inhibition of S6K1 either indirectly with rapamycin or directly with PF-4708671 diminished the offline improvement in motor performance without affecting the initial acquisition of rotarod motor learning when sleep is normal. In sum, S6K1 activity is required for sleep-dependent offline gains in motor performance and is inhibited following acute sleep disruption, while motor learning increases the abundance of striatal RpS6. Thus, S6K1 signaling represents a plausible mechanism mediating the beneficial effects of sleep on motor performance.
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Targeting Translation Control with p70 S6 Kinase 1 Inhibitors to Reverse Phenotypes in Fragile X Syndrome Mice
Neuropsychopharmacology, 2016Co-Authors: Aditi Bhattacharya, Maggie Mamcarz, Caitlin Mullins, Ayesha Choudhury, Robert G Boyle, Daniel G Smith, David W Walker, Eric KlannAbstract:Aberrant neuronal translation is implicated in the etiology of numerous brain disorders. Although mTORC1-p70 ribosomal S6 Kinase 1 (S6K1) signaling is critical for translational control, pharmacological manipulation in vivo has targeted exclusively mTORC1 due to the paucity of specific inhibitors to S6K1. However, small molecule inhibitors of S6K1 could potentially ameliorate pathological phenotypes of diseases, which are based on aberrant translation and protein expression. One such condition is fragile X syndrome (FXS), which is considered to be caused by exaggerated neuronal translation and is the most frequent heritable cause of autism spectrum disorder (ASD). To date, potential therapeutic interventions in FXS have focused largely on targets upstream of translational control to normalize FXS-related phenotypes. Here we test the ability of two S6K1 inhibitors, PF-4708671 and FS-115, to normalize translational homeostasis and other phenotypes exhibited by FXS model mice. We found that although the pharmacokinetic profiles of the two S6K1 inhibitors differed, they overlapped in reversing multiple disease-associated phenotypes in FXS model mice including exaggerated protein synthesis, inappropriate social behavior, behavioral inflexibility, altered dendritic spine morphology, and macroorchidism. In contrast, the two inhibitors differed in their ability to rescue stereotypic marble-burying behavior and weight gain. These findings provide an initial pharmacological characterization of the impact of S6K1 inhibitors in vivo for FXS, and have therapeutic implications for other neuropsychiatric conditions involving aberrant mTORC1-S6K1 signaling.
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Calmodulin activity regulates group I metabotropic glutamate receptor‐mediated signal transduction and synaptic depression
Journal of Neuroscience Research, 2016Co-Authors: Ferzin Sethna, Eric Klann, Hanoch Kaphzan, Ming Zhang, Dawn M. Autio, Charles L. Cox, Hongbing WangAbstract:Group I metabotropic glutamate receptors (mGluR), including mGluR1 and mGluR 5 (mGluR1/5), are coupled to Gq and modulate activity-dependent synaptic plasticity. Direct activation of mGluR1/5 causes protein translation-dependent long-term depression (LTD). Although it has been established that intracellular Ca(2+) and the Gq-regulated signaling molecules are required for mGluR1/5 LTD, whether and how Ca(2+) regulates Gq signaling and upregulation of protein expression remain unknown. Through pharmacological inhibition, we tested the function of the Ca(2+) sensor calmodulin (CaM) in intracellular signaling triggered by the activation of mGluR1/5. CaM inhibitor N-[4-aminobutyl]-5-chloro-2-naphthalenesulfonamide hydrochloride (W13) suppressed the mGluR1/5-stimulated activation of extracellular signal-regulated Kinase 1/2 (ERK1/2) and P70-S6 Kinase 1 (S6K1) in hippocampal neurons. W13 also blocked the mGluR1/5 agonist-induced synaptic depression in hippocampal slices and in anesthetized mice. Consistent with the function of CaM, inhibiting the downstream targets Ca(2+) /CaM-dependent protein Kinases (CaMK) blocked ERK1/2 and S6K1 activation. Furthermore, disruption of the CaM-CaMK-ERK1/2 signaling cascade suppressed the mGluR1/5-stimulated upregulation of Arc expression. Altogether, our data suggest CaM as a new Gq signaling component for coupling Ca(2+) and protein upregulation and regulating mGluR1/5-mediated synaptic modification.
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Genetic Removal of p70 S6 Kinase 1 Corrects Molecular, Synaptic, and Behavioral Phenotypes in Fragile X Syndrome Mice
Neuron, 2012Co-Authors: Aditi Bhattacharya, Hanoch Kaphzan, Amanda C. Alvarez-dieppa, Jaclyn P. Murphy, Philippe Pierre, Eric KlannAbstract:Fragile X syndrome (FXS) is the leading inherited cause of autism and intellectual disability. Aberrant synaptic translation has been implicated in the etiology of FXS, but most lines of research on therapeutic strategies have targeted protein synthesis indirectly, far upstream of the translation machinery. We sought to perturb p70 ribosomal S6 Kinase 1 (S6K1), a key translation initiation and elongation regulator, in FXS model mice. We found that genetic reduction of S6K1 prevented elevated phosphorylation of translational control molecules, exaggerated protein synthesis, enhanced mGluR-dependent long-term depression (LTD), weight gain, and macro-orchidism in FXS model mice. In addition, S6K1 deletion prevented immature dendritic spine morphology and multiple behavioral phenotypes, including social interaction deficits, impaired novel object recognition, and behavioral inflexibility. Our results support the model that dysregulated protein synthesis is the key causal factor in FXS and that restoration of normal translation can stabilize peripheral and neurological function in FXS.
Shile Huang - One of the best experts on this subject based on the ideXlab platform.
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Abstract 2961: Ganoderma lucidum extracts inhibit mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells
Experimental and Molecular Therapeutics, 2019Co-Authors: Shile Huang, Didem Sohretoglu, Chao Zhang, Jun LuoAbstract:Ganoderma lucidum (G. lucidum) extracts, as dietary supplements, have been found to possess potent anticancer activity, which is attributed to the presence of polysaccharides and triterpenes. However, the molecular mechanism underlying the anticancer action of G. lucidum extracts remains to be elucidated. Here we show that ReishiMax GLp, containing both polysaccharides and triterpenes of G. lucidum (GLPT), inhibited cell proliferation and induced cell death in human lung cancer cells (A549 and A427), and concurrently suppressed the signaling pathways mediated by the mammalian target of rapamycin (mTOR), a central regulator of cell proliferation and survival. Interestingly, GLPT not only inhibited mTORC1-mediated phosphorylation of p70 S6 Kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), but also repressed mTORC2-mediated phosphorylation of Akt. Mechanistically, GLPT downregulated the phosphorylation and protein levels of insulin-like growth factor 1 receptor (IGFR) and phosphoinositide 3-Kinase (PI3K), as well as the protein level of RAS homolog enriched in brain (Rheb). Besides, GLPT also activated AMP-activated protein Kinase (AMPK) network. This is supported by the findings that GLPT increased the phosphorylation of AMPKα (T172), as well as its substrates tuberous sclerosis complex 2 (TSC2, S1387) and regulatory-associated protein of mTOR (raptor, S792). Ectopic expression of dominant negative AMPKα partially attenuated the inhibitory effect of GLPT on mTORC1, indicating that GLPT inhibits mTORC1 partly via activating AMPK. The results suggest that G. lucidum extracts execute the anticancer action at least partly by inhibiting the mTORC1/2 signaling through activation of AMPK and inhibition of IGFR/PI3K/Rheb in tumor cells. Supported by the Feist-Weiller Cancer Center, LSU Health Sciences Center, Shreveport, LA, USA. Citation Format: Shile Huang, Didem Sohretoglu, Chao Zhang, Jun Luo. Ganoderma lucidum extracts inhibit mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2961.
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Rapamycin inhibits mSin1 phosphorylation independently of mTORC1 and mTORC2
Oncotarget, 2015Co-Authors: Yan Luo, Lei Liu, Karnika Singh, Nan Zhang, Xiaowei Liu, Yangmei Shen, Shile HuangAbstract:// Yan Luo 1, 2, 3, * , Lei Liu 2, * , Yang Wu 1, 2 , Karnika Singh 2 , Bing Su 4 , Nan Zhang 1 , Xiaowei Liu 1 , Yangmei Shen 1 , Shile Huang 2, 3 1 State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China 2 Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA 3 Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA 4 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA * These authors have contributed equally to this work Correspondence to: Shile Huang, e-mail: shuan1@lsuhsc.edu Keywords: Rapamycin, mTOR, mSin1, raptor, rictor Received: November 19, 2014 Accepted: December 21, 2014 Published: January 30, 2015 ABSTRACT Current knowledge indicates that the mammalian target of rapamycin (mTOR) functions as two complexes, mTORC1 and mTORC2, regulating cell growth, proliferation, survival, differentiation, and motility. Recently mSin1 has been identified as a critical component of mTORC2, which is essential for phosphorylation of Akt and other signaling molecules. Studies have shown that rapamycin inhibits phosphorylation of mSin1. However, the underlying mechanism is unknown. Here we found that rapamycin inhibited phosphorylation of mSin1 potently and rapidly. Expression of rapamycin-resistant mutant of mTOR (mTOR-T), but not rapamycin-resistant and Kinase dead mutant of mTOR (mTOR-TE), prevented rapamycin from inhibiting mSin1 phosphorylation, suggesting that rapamycin-induced dephosphorylation of mSin1 is mTOR-dependent. Surprisingly, ectopic expression of rapamycin-resistant and constitutively active p70 S6 Kinase 1 (S6K1) did not confer resistance to rapamycin-induced dephosphorylation of mSin1. Furthermore, disruption of mTORC1 and mTORC2 by silencing raptor and rictor, respectively, or downregulation of S6K1 or Akt did not induce the dephosphorylation of mSin1 as rapamycin did. However, silencing mTOR or mLST8 mimicked the effect of rapamycin, inhibiting mSin1 phosphorylation. Our findings suggest that rapamycin inhibits mSin1 phosphorylation, which is independent of mTORC1 and mTORC2, but is possibly dependent on a new mTOR complex, which at least contains mTOR and mLST8.
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Abstract 4354: Dihydroartemisinin inhibits mTORC1 signaling in tumor cells.
Experimental and Molecular Therapeutics, 2013Co-Authors: Yoshinobu Odaka, Shile HuangAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Dihydroartemisinin (DHA) is a derivative of artemisinin, a natural product isolated from the plant, Artemisia annua. DHA is also the active metabolite of first-generation artemisinin derivatives (artemisinin, artesunate, artemether, etc.). Artemisinins have been clinically used to treat malaria for decades. Recent studies have demonstrated that artemisinin and its derivatives possess anticancer activity. This study was set to investigate the anticancer mechanism of DHA. We found that DHA inhibited proliferation in a spectrum of tumor cells, by arresting cells in G1/G0 and G2/M phases, which was linked to downregulation of cyclin D1, CDK4 and CDC25A, as well as CDK1 and CDC25C expression, respectively. We also observed that DHA induced caspase-dependent apoptosis, which was related to downregulation of survivin, Mcl-1 and Bcl2. As the mammalian target of rapamycin (mTOR) is a master Kinase that regulates cell proliferation and survival, we further tested whether DHA inhibits mTOR signaling. Interestingly, we observed that DHA inhibited phosphoryaltion of mTOR and its downstream effector molecules, p70 S6 Kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), in a concentration- and time-dependent manner, but did not obviously affect mTORC2-mediated phosphorylation of Akt, which is in contrast to the conventional mTORC1 inhibitor, rapamycin. The results suggest that DHA may represent a novel class of mTORC1 inhibitor, and may execute its anticancer activity primarily by blocking mTOR-mediated signaling pathways in the tumor cells. Citation Format: Yoshinobu Odaka, Baoshan Xu, Shile Huang. Dihydroartemisinin inhibits mTORC1 signaling in tumor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4354. doi:10.1158/1538-7445.AM2013-4354
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Abstract 5379: Ciclopirox induces autophagy through reactive oxygen species-mediated inhibition of mTOR signaling pathway
Experimental and Molecular Therapeutics, 2011Co-Authors: Hongyu Zhou, Shile HuangAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Ciclopirox olamine (CPX), a synthetic antifungal agent clinically used to treat mycoses of the skin and nails, has been recently found to inhibit tumor growth in mouse model of leukemia and breast cancer MDA-MB231. The mammalian target of rapamycin (mTOR), an evolutionarily conserved serine/threonine Kinase, is known as a negative regulator of autophagy. Herein, we found that CPX substantially increased GFP-LC3 dots and expression of LC3-II, a hallmark of autophagy, suggesting that CPX induced autophagy. Meanwhile, we discovered that CPX inhibited mTOR signaling in different cancer cell lines, as evidenced by reduced phosphorylation of the downstream targets of mTOR, p70 S6 Kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1). Recently, it has been demonstrated that autophagy can be induced by reactive oxygen species (ROS). Interestingly, we further found that CPX treatment dose-dependently induced ROS generation. Pretreatment with N-acetyl-L-cysteine (NAC) suppressed CPX-induced ROS and the conversion of LC3I to LC3II, suggesting that CPX-induced autophagy is mediated by ROS generation. Moreover, the inhibition of phosphorylation of S6K1 and 4E-BP1 by CPX were partially rescued by NAC pretreatment as well. These data suggest that CPX-induced autophagy may be attributed to induction of ROS and subsequent inhibition of mTOR signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5379. doi:10.1158/1538-7445.AM2011-5379
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Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death.
Free Radical Biology and Medicine, 2011Co-Authors: Long Chen, Wenxing Chen, Yan Luo, Lei Liu, Hongyu Zhou, Xiuzhen Han, Tao Shen, Christopher D. Kontos, Shile HuangAbstract:Abstract Cadmium (Cd), a highly toxic environmental pollutant, induces neurodegenerative diseases. Recently we have demonstrated that Cd induces neuronal apoptosis in part through activation of the mammalian target of rapamycin (mTOR) pathway. However, the underlying mechanism is unknown. Here we show that Cd induces the generation of reactive oxygen species (ROS) by upregulating the expression of NADPH oxidase 2 and its regulatory proteins (p22phox, p67phox, p40phox, p47phox, and Rac1) in PC12 and SH-SY5Y cells. Cd induction of ROS contributed to the activation of mTOR signaling, as pretreatment with N-acetyl- l -cysteine (NAC), a ROS scavenger, prevented this event. Further studies reveal that Cd induction of ROS increased phosphorylation of the type I insulin-like growth factor receptor (IGFR) β subunit, which was abrogated by NAC. Wortmannin, a phosphoinositide 3′-Kinase (PI3K) inhibitor, partially attenuated Cd-induced phosphorylation of Akt, p70 S6 Kinase 1, and eukaryotic initiation factor 4E-binding protein 1, as well as apoptosis of the neuronal cells. In addition, overexpression of wild-type phosphatase and tensin homologue deleted on chromosome 10 (PTEN) or pretreatment with aminoimidazole carboxamide ribonucleotide, an AMP-activated protein Kinase (AMPK) activator, partially prevented Cd-induced ROS and activation of the mTOR pathway, as well as cell death. The results indicate that Cd induction of ROS activates mTOR signaling, leading to neuronal cell death, in part by activating the positive regulators IGFR/PI3K and by inhibiting the negative regulators PTEN/AMPK. The findings suggest that inhibitors of PI3K and mTOR, activators of AMPK, or antioxidants may be exploited for the prevention of Cd-induced neurodegenerative diseases.
Fei Zhao - One of the best experts on this subject based on the ideXlab platform.
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gambogic acid induces g0 g1 arrest and apoptosis involving inhibition of src 3 and inactivation of akt pathway in k562 leukemia cells
Toxicology, 2009Co-Authors: Rui Li, Yan Chen, Linglan Zeng, Fei ZhaoAbstract:Abstract Gambogic acid (GA), a major active component of gamboge, exhibits potent anticancer activity in many kinds of cancer cells. However, the anticancer mechanism of GA is not clearly understood. Here we showed that GA could cause growth inhibition, induce the G0/G1 phase cell cycle arrest and apoptosis in human chronic myelogenous leukemia cell line K562 cells. Since steroid receptor coactivator-3 (SRC-3), overexpressed in many human malignancies including leukemia, is a central target for cancer therapy, we also explored the effects of GA on SRC-3 and SRC-3-regulated gene products in K562. GA treatment downregulated the expression of SRC-3 and then inhibited the activity of Akt Kinase and its downstream targets p70 S6 Kinase 1 (S6K1) and glycogen synthase Kinase 3β (GSK3β) without changes in total protein levels of these three proteins, which thus influenced the expression of the apoptosis related gene Bcl-2 in K562 cells. These results suggest that GA might exhibit its strong antitumor effects via the interruption of SRC-3.
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Gambogic acid induces G0/G1 arrest and apoptosis involving inhibition of SRC-3 and inactivation of Akt pathway in K562 leukemia cells
Toxicology, 2009Co-Authors: Yan Chen, Linglan Zeng, Fei Zhao, Wenxiu Shu, Lu Wen, Yuan LiuAbstract:Abstract Gambogic acid (GA), a major active component of gamboge, exhibits potent anticancer activity in many kinds of cancer cells. However, the anticancer mechanism of GA is not clearly understood. Here we showed that GA could cause growth inhibition, induce the G0/G1 phase cell cycle arrest and apoptosis in human chronic myelogenous leukemia cell line K562 cells. Since steroid receptor coactivator-3 (SRC-3), overexpressed in many human malignancies including leukemia, is a central target for cancer therapy, we also explored the effects of GA on SRC-3 and SRC-3-regulated gene products in K562. GA treatment downregulated the expression of SRC-3 and then inhibited the activity of Akt Kinase and its downstream targets p70 S6 Kinase 1 (S6K1) and glycogen synthase Kinase 3β (GSK3β) without changes in total protein levels of these three proteins, which thus influenced the expression of the apoptosis related gene Bcl-2 in K562 cells. These results suggest that GA might exhibit its strong antitumor effects via the interruption of SRC-3.
Aditi Bhattacharya - One of the best experts on this subject based on the ideXlab platform.
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Targeting Translation Control with p70 S6 Kinase 1 Inhibitors to Reverse Phenotypes in Fragile X Syndrome Mice
Neuropsychopharmacology, 2016Co-Authors: Aditi Bhattacharya, Maggie Mamcarz, Caitlin Mullins, Ayesha Choudhury, Robert G Boyle, Daniel G Smith, David W Walker, Eric KlannAbstract:Aberrant neuronal translation is implicated in the etiology of numerous brain disorders. Although mTORC1-p70 ribosomal S6 Kinase 1 (S6K1) signaling is critical for translational control, pharmacological manipulation in vivo has targeted exclusively mTORC1 due to the paucity of specific inhibitors to S6K1. However, small molecule inhibitors of S6K1 could potentially ameliorate pathological phenotypes of diseases, which are based on aberrant translation and protein expression. One such condition is fragile X syndrome (FXS), which is considered to be caused by exaggerated neuronal translation and is the most frequent heritable cause of autism spectrum disorder (ASD). To date, potential therapeutic interventions in FXS have focused largely on targets upstream of translational control to normalize FXS-related phenotypes. Here we test the ability of two S6K1 inhibitors, PF-4708671 and FS-115, to normalize translational homeostasis and other phenotypes exhibited by FXS model mice. We found that although the pharmacokinetic profiles of the two S6K1 inhibitors differed, they overlapped in reversing multiple disease-associated phenotypes in FXS model mice including exaggerated protein synthesis, inappropriate social behavior, behavioral inflexibility, altered dendritic spine morphology, and macroorchidism. In contrast, the two inhibitors differed in their ability to rescue stereotypic marble-burying behavior and weight gain. These findings provide an initial pharmacological characterization of the impact of S6K1 inhibitors in vivo for FXS, and have therapeutic implications for other neuropsychiatric conditions involving aberrant mTORC1-S6K1 signaling.
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Genetic Removal of p70 S6 Kinase 1 Corrects Molecular, Synaptic, and Behavioral Phenotypes in Fragile X Syndrome Mice
Neuron, 2012Co-Authors: Aditi Bhattacharya, Hanoch Kaphzan, Amanda C. Alvarez-dieppa, Jaclyn P. Murphy, Philippe Pierre, Eric KlannAbstract:Fragile X syndrome (FXS) is the leading inherited cause of autism and intellectual disability. Aberrant synaptic translation has been implicated in the etiology of FXS, but most lines of research on therapeutic strategies have targeted protein synthesis indirectly, far upstream of the translation machinery. We sought to perturb p70 ribosomal S6 Kinase 1 (S6K1), a key translation initiation and elongation regulator, in FXS model mice. We found that genetic reduction of S6K1 prevented elevated phosphorylation of translational control molecules, exaggerated protein synthesis, enhanced mGluR-dependent long-term depression (LTD), weight gain, and macro-orchidism in FXS model mice. In addition, S6K1 deletion prevented immature dendritic spine morphology and multiple behavioral phenotypes, including social interaction deficits, impaired novel object recognition, and behavioral inflexibility. Our results support the model that dysregulated protein synthesis is the key causal factor in FXS and that restoration of normal translation can stabilize peripheral and neurological function in FXS.
J Downward - One of the best experts on this subject based on the ideXlab platform.
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Rictor is a novel target of p70 S6 Kinase-1
Oncogene, 2010Co-Authors: C Treins, P H Warne, M A Magnuson, M Pende, J DownwardAbstract:The rapamycin-insensitive companion of mammalian target of rapamycin (mTOR) (Rictor) is a key member of mTOR complex-2 (mTORC2), which phosphorylates the AGC Kinases Akt/PKB, PKC and SGK1 at a C-terminal hydrophobic motif. We identified several novel sites on Rictor that are phosphorylated, including Thr1135, which is conserved across all vertebrates. Phosphorylation of this site on Rictor is stimulated by amino acids and growth factors through a rapamycin-sensitive signaling cascade. We demonstrate here that Rictor is a direct target of the ribosomal protein S6 Kinase-1 (S6K1). Rictor phosphorylation at Thr1135 does not lead to major changes in mTORC2-Kinase activity. However, phosphorylation of this site turns over rapidly and mediates 14-3-3 binding to Rictor and mTORC2, providing possibility for altered interactions of the complex. These findings reveal an unexpected signaling input into mTORC2, which is regulated by amino acids, growth factors and rapamycin.
