DOCSLIB.ORG

Elevated ERK/P90 Ribosomal S6 Kinase Activity Underlies PNAS PLUS Audiogenic Seizure Susceptibility in Fragile X Mice

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Elevated ERK/P90 Ribosomal S6 Kinase Activity Underlies PNAS PLUS Audiogenic Seizure Susceptibility in Fragile X Mice Elevated ERK/p90 ribosomal S6 kinase activity underlies PNAS PLUS audiogenic seizure susceptibility in fragile X mice Kirsty Sawickaa,1,2,3, Alexander Pyronneaua,1, Miranda Chaoa, Michael V. L. Bennetta,3, and R. Suzanne Zukina,3 aDominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461 Contributed by Michael V. L. Bennett, August 8, 2016 (sent for review June 24, 2016; reviewed by Leonard K. Kaczmarek and Siqiong June Liu) Fragile X syndrome (FXS) is the most common heritable cause of protein synthesis (∼15–20%) suggests that secondary effects on intellectual disability and a leading genetic form of autism. The translation are also involved (9). Consistent with this finding, FMRP Fmr1 KO mouse, a model of FXS, exhibits elevated translation in targets include components of ERK (extracellular signal-regulated the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling and kinase) and mTOR (mechanistic target of rapamycin) signaling reg- proteins involved in translation initiation and elongation (2). ulate protein synthesis by activating downstream targets critical to PI3K/Akt/mTOR signaling is overactivated in the hippocam- translation initiation and elongation and are known to contribute pus of Fmr1 KO mice (10, 11). Genetic and pharmacological to hippocampal defects in fragile X. Here we show that the effect of interventions that reduce the activity of PI3-kinase (PI3K) or the loss of fragile X mental retardation protein (FMRP) on these path- downstream effector S6 kinase (S6K) have both shown promise ways is brain region specific. In contrast to the hippocampus, ERK for the rescue of disease-relevant phenotypes in the Fmr1 KO (but not mTOR) signaling is elevated in the neocortex of fragile X mouse (12, 13). In contrast, ERK signaling appears normal in mice. Phosphorylation of ribosomal protein S6, typically a down- the hippocampus with no change in basal or activated levels of stream target of mTOR, is elevated in the neocortex, despite normal protein phosphorylation (10, 14). However, emerging evidence mTOR activity. This is significant in that S6 phosphorylation facili- supports the concept that loss of FMRP can lead to synaptic de- tates translation, correlates with neuronal activation, and is altered fects that differ in an age-, synapse-, cell-, and/or brain region- in neurodevelopmental disorders. We show that in fragile X mice, specific manner as, for example, synapse-specific defects in synaptic S6 is regulated by ERK via the “alternative” S6 kinase p90-ribosomal plasticity (15), inhibitory circuit dysfunction (16), and dendritic spine S6 kinase (RSK), as evidenced by the site of elevated phosphoryla- morphology (17). Thus, the present study was undertaken to examine NEUROSCIENCE tion and the finding that ERK inhibition corrects elevated RSK and the hypothesis that aberrant ERK signaling outside of the hippo- S6 activity. These findings indicate that signaling networks are al- campus may contribute to synaptic phenotypes in fragile X mice. tered in the neocortex of fragile X mice such that S6 phosphoryla- Here we show that whereas mTOR signaling is elevated at syn- tion receives aberrant input from ERK/RSK. Importantly, an RSK apses of the hippocampus (11), ERK (but not mTOR) signaling is inhibitor reduces susceptibility to audiogenic seizures in fragile X elevated at synapses of the neocortex of Fmr1 KO mice. We further mice. Our findings identify RSK as a therapeutic target for fragile X show that phosphorylation of ribosomal protein S6, typically a and suggest the therapeutic potential of drugs for the treatment of target and downstream effector of mTOR, is elevated and lies FXS may vary in a brain-region–specific manner. downstream of ERK via the “alternative” S6 kinase p90-ribosomal S6 kinase (RSK), providing evidence of a noncanonical signaling intellectual disability | autism | mTOR | FMRP | RSK pathway. Consistent with this, the brain-penetrant RSK inhibitor, BI-D1870, prevents audiogenic seizures, a hallmark feature of ragile X syndrome (FXS) is the most common heritable form Fof intellectual disability and a leading genetic cause of autism. Significance Individuals with FXS typically suffer from a range of cognitive and behavioral deficits that can include anxiety, stereotypic move- Fragile X syndrome is the most common heritable cause of in- ments, hyperactivity, seizures, and aggression, as well as social tellectual disability and autism. Elevated protein synthesis is con- deficits typical of autism (1). FXS is caused by transcriptional si- sidered a major contributor to the pathophysiology of fragile FMR1 lencing or mutation of the gene encoding the RNA-binding X. ERK (extracellular signal-regulated kinase) and mTOR (mecha- protein, FMRP (fragile X mental retardation protein). FMRP nistic target of rapamycin) are key signaling molecules in two > binds to 1,000 mRNAs, including transcripts encoding both pre- prominent pathways that regulate protein synthesis. A major and postsynaptic proteins important for synaptic function, and finding of this study is that ERK (but not mTOR) signaling is ele- represses their translation via ribosome stalling (2). Loss of FMRP vated in the neocortex of fragile X mice. Elevated ERK activity expression in fragile X syndrome would be expected to cause causes overactivation of p90-ribosomal S6 kinase (RSK) and translational derepression of these target mRNAs. hyperphosphorylation of ribosomal protein S6. Audiogenic sei- FMRP is strategically localized to dendrites, dendritic spines, zures in fragile X mice, which mimic sensory hypersensitivity in axons, and cell bodies to control protein synthesis. Loss of FMRP fragile X humans, are prevented by RSK inhibition. Thus, RSK is causes enhanced protein synthesis, which can lead to altered spine a potential therapeutic target for treatment of fragile X. morphology, synaptic circuits, and synaptic function with robust effects on higher cognitive function. The excessive, unchecked Author contributions: K.S., A.P., M.V.L.B., and R.S.Z. conceived and designed research; protein synthesis and impaired stimulus-induced protein synthesis K.S., A.P., and M.C., performed research, collected and assembled the data; K.S., A.P., M.C., M.V.L.B., and R.S.Z. analyzed and interpreted data; and K.S., A.P., M.C., M.V.L.B., are considered to be major contributors to the pathophysiology of and R.S.Z. wrote and approved the final manuscript. fragile X (3–5). Increased protein synthesis has been demon- Fmr1 Reviewers: L.K.K., Yale University School of Medicine; and S.J.L., Louisiana State University strated in whole-animal studies in fragile X mice ( KO) that Health Sciences Center. model the loss of FMRP function responsible for the human The authors declare no conflict of interest. disorder (6), brain slices from fragile X mice (7), and cell cultures 1K.S. and A.P. contributed equally to this work. from human subjects with fragile X (8). FMRP directly regulates 2Present address: Laboratory of Molecular Neuro-Oncology, The Rockefeller University, the translation of a specific subset of target mRNAs. Given that New York, NY 10065. ∼ these represent 5% of all mRNAs and are relatively low-abun- 3To whom correspondence may be addressed. Email: [email protected], suzanne. dance transcripts, the magnitude of the observed increase in global [email protected], or [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1610812113 PNAS Early Edition | 1of8 Downloaded by guest on October 1, 2021 sensory hypersensitivity in fragile X mice. These findings provide A E evidence of disease-dependent alterations of the ERK/RSK sig- pSer217/221-MEK pThr308-Akt naling network in the neocortex of fragile X mice. WT KO WT KO p-MEK 45 kDa p-Akt 60 kDa Results MEK 45 kDa Akt 60 kDa ERK but Not mTOR Signaling Is Elevated in the Cortex of Fmr1 KO GAPDH 37 kDa GAPDH 37 kDa Mice. Elevated protein synthesis is a hallmark feature of Fmr1 p-MEK Total MEK p-Akt Total Akt KO mice (13, 18, 19). The ERK/MAPK and mTOR pathways are two critical signaling pathways that regulate protein synthesis 1 * 1 1 1 in the brain and have been implicated in the pathophysiology of p-Akt/Akt Akt/GAPDH p-MEK/MEK 0 MEK/GAPDH 0 0 0 fragile X (3, 4). We focused on the neocortex, because neocortical WT KO WT KO KOWT KOWT network activity is enhanced in fragile X (20), and protein- synthesis–dependent synaptic plasticity is impaired in the fragile B F X cortex (21). ERK/MAPK signaling is initiated by activation of pThr185/Tyr187-ERK pSer2448-mTOR Ras, which phosphorylates the protein kinase MEK. We first WT KO WT KO examined the phosphorylation status and abundance of the up- p-ERK1/2 42/44 kDa p-mTOR 289 kDa stream kinase MEK, which phosphorylates and activates ERK, in ERK1/2 42/44 kDa mTOR 289 kDa the neocortex of young fragile X mice. Phosphorylation of MEK GAPDH 37 kDa GAPDH 37 kDa at Ser217/221 showed a small yet significant increase, indicative p-ERK1/2 Total ERK1/2 p-mTOR Total mTOR of activation, in whole-cell lysates isolated from the neocortex of 4-wk-old Fmr1 KO mice vs. wild-type littermates with little or no **** 1 1 1 1 change in total MEK abundance (Fig. 1A). We next examined the phosphorylation status and abundance of the downstream mTOR/GAPDH ERK1/2/GAPDH 0 0 p-mTOR/mTOR 0 0 target of MEK, ERK1/2, in young fragile X mice. Phosphoryla- p-ERK1/2/ERK1/2 WT KO WT KO WT KO KOWT tion of ERK1/2 at Thr185/Tyr187 was elevated, indicative of activation, in whole-cell lysates from the neocortex of 4-wk-old C pThr195/202-MNK G pThr37/46-4EBP Fmr1 KO mice relative to that of control littermates, with little WT KO WT KO or no change in total ERK abundance (Fig.
Load more

Recommended publications
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Genome-Wide DNA Methylation Analysis of KRAS Mutant Cell Lines Ben Yi Tew1,5, Joel K
    www.nature.com/scientificreports OPEN Genome-wide DNA methylation analysis of KRAS mutant cell lines Ben Yi Tew1,5, Joel K. Durand2,5, Kirsten L. Bryant2, Tikvah K. Hayes2, Sen Peng3, Nhan L. Tran4, Gerald C. Gooden1, David N. Buckley1, Channing J. Der2, Albert S. Baldwin2 ✉ & Bodour Salhia1 ✉ Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest that DNA methylation changes may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of DNA methylation events associated with oncogenic KRAS expression could enhance therapeutic approaches. Here we analyzed the basal CpG methylation of 11 KRAS-mutant and dependent pancreatic cancer cell lines and observed strikingly similar methylation patterns. KRAS knockdown resulted in unique methylation changes with limited overlap between each cell line. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 diferentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS G12V overexpression in an isogenic lung model reveals >50,600 DM CpGs compared to non-transformed controls. In lung and pancreatic cells, gene ontology analyses of DM promoters show an enrichment for genes involved in diferentiation and development. Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream efector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer. Activating KRAS mutations can be found in nearly 25 percent of all cancers1.
    [Show full text]
  • WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C12Q 1/68 (2018.01) A61P 31/18 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, C12Q 1/70 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US2018/056167 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 16 October 2018 (16. 10.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/573,025 16 October 2017 (16. 10.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, (71) Applicant: MASSACHUSETTS INSTITUTE OF MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Cambridge, Massachusetts 02139 (US).
    [Show full text]
  • X-Linked Diseases: Susceptible Females
    REVIEW ARTICLE X-linked diseases: susceptible females Barbara R. Migeon, MD 1 The role of X-inactivation is often ignored as a prime cause of sex data include reasons why women are often protected from the differences in disease. Yet, the way males and females express their deleterious variants carried on their X chromosome, and the factors X-linked genes has a major role in the dissimilar phenotypes that that render women susceptible in some instances. underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the Genetics in Medicine (2020) 22:1156–1174; https://doi.org/10.1038/s41436- heart, blood, skin, muscle, and bones. Summarized here are many 020-0779-4 examples of the different presentations in males and females. Other INTRODUCTION SEX DIFFERENCES ARE DUE TO X-INACTIVATION Sex differences in human disease are usually attributed to The sex differences in the effect of X-linked pathologic variants sex specific life experiences, and sex hormones that is due to our method of X chromosome dosage compensation, influence the function of susceptible genes throughout the called X-inactivation;9 humans and most placental mammals – genome.1 5 Such factors do account for some dissimilarities. compensate for the sex difference in number of X chromosomes However, a major cause of sex-determined expression of (that is, XX females versus XY males) by transcribing only one disease has to do with differences in how males and females of the two female X chromosomes. X-inactivation silences all X transcribe their gene-rich human X chromosomes, which is chromosomes but one; therefore, both males and females have a often underappreciated as a cause of sex differences in single active X.10,11 disease.6 Males are the usual ones affected by X-linked For 46 XY males, that X is the only one they have; it always pathogenic variants.6 Females are biologically superior; a comes from their mother, as fathers contribute their Y female usually has no disease, or much less severe disease chromosome.
    [Show full text]
  • High Constitutive Cytokine Release by Primary Human Acute Myeloid Leukemia Cells Is Associated with a Specific Intercellular Communication Phenotype
    Supplementary Information High Constitutive Cytokine Release by Primary Human Acute Myeloid Leukemia Cells Is Associated with a Specific Intercellular Communication Phenotype Håkon Reikvam 1,2,*, Elise Aasebø 1, Annette K. Brenner 2, Sushma Bartaula-Brevik 1, Ida Sofie Grønningsæter 2, Rakel Brendsdal Forthun 2, Randi Hovland 3,4 and Øystein Bruserud 1,2 1 Department of Clinical Science, University of Bergen, 5020, Bergen, Norway 2 Department of Medicine, Haukeland University Hospital, 5021, Bergen, Norway 3 Department of Medical Genetics, Haukeland University Hospital, 5021, Bergen, Norway 4 Institute of Biomedicine, University of Bergen, 5020, Bergen, Norway * Correspondence: [email protected]; Tel.: +55-97-50-00 J. Clin. Med. 2019, 8, x 2 of 36 Figure S1. Mutational studies in a cohort of 71 AML patients. The figure shows the number of patients with the various mutations (upper), the number of mutations in for each patient (middle) and the number of main classes with mutation(s) in each patient (lower). 2 J. Clin. Med. 2019, 8, x; doi: www.mdpi.com/journal/jcm J. Clin. Med. 2019, 8, x 3 of 36 Figure S2. The immunophenotype of primary human AML cells derived from 62 unselected patients. The expression of the eight differentiation markers CD13, CD14, CD15, CD33, CD34, CD45, CD117 and HLA-DR was investigated for 62 of the 71 patients included in our present study. We performed an unsupervised hierarchical cluster analysis and identified four patient main clusters/patient subsets. The mutational profile for each f the 62 patients is also given (middle), no individual mutation of main class of mutations showed any significant association with any of the for differentiation marker clusters (middle).
    [Show full text]
  • Characterization of the Small Molecule Kinase Inhibitor SU11248 (Sunitinib/ SUTENT in Vitro and in Vivo
    TECHNISCHE UNIVERSITÄT MÜNCHEN Lehrstuhl für Genetik Characterization of the Small Molecule Kinase Inhibitor SU11248 (Sunitinib/ SUTENT in vitro and in vivo - Towards Response Prediction in Cancer Therapy with Kinase Inhibitors Michaela Bairlein Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ. -Prof. Dr. K. Schneitz Prüfer der Dissertation: 1. Univ.-Prof. Dr. A. Gierl 2. Hon.-Prof. Dr. h.c. A. Ullrich (Eberhard-Karls-Universität Tübingen) 3. Univ.-Prof. A. Schnieke, Ph.D. Die Dissertation wurde am 07.01.2010 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 19.04.2010 angenommen. FOR MY PARENTS 1 Contents 2 Summary ................................................................................................................................................................... 5 3 Zusammenfassung .................................................................................................................................................... 6 4 Introduction .............................................................................................................................................................. 8 4.1 Cancer ..............................................................................................................................................................
    [Show full text]
  • Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease
    Supplementary Online Content Ganz P, Heidecker B, Hveem K, et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. doi: 10.1001/jama.2016.5951 eTable 1. List of 1130 Proteins Measured by Somalogic’s Modified Aptamer-Based Proteomic Assay eTable 2. Coefficients for Weibull Recalibration Model Applied to 9-Protein Model eFigure 1. Median Protein Levels in Derivation and Validation Cohort eTable 3. Coefficients for the Recalibration Model Applied to Refit Framingham eFigure 2. Calibration Plots for the Refit Framingham Model eTable 4. List of 200 Proteins Associated With the Risk of MI, Stroke, Heart Failure, and Death eFigure 3. Hazard Ratios of Lasso Selected Proteins for Primary End Point of MI, Stroke, Heart Failure, and Death eFigure 4. 9-Protein Prognostic Model Hazard Ratios Adjusted for Framingham Variables eFigure 5. 9-Protein Risk Scores by Event Type This supplementary material has been provided by the authors to give readers additional information about their work. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Supplemental Material Table of Contents 1 Study Design and Data Processing ......................................................................................................... 3 2 Table of 1130 Proteins Measured .......................................................................................................... 4 3 Variable Selection and Statistical Modeling ........................................................................................
    [Show full text]
  • Updates in Tumor Profiling in Gastrointestinal Cancers
    UPDATES IN ONCOLOGY: PART 1 Updates in Tumor Profiling in Gastrointestinal Cancers KIMBERLY PEREZ, MD; HOWARD SAFRAN MD 21 24 EN ABSTRACT TUMOR TYPES AND MUTATIONS In the last decade there has been a focus on biomarkers Colorectal Cancer that play a critical role in understanding molecular and Sjoblom and Wood and colleagues were the first to perform cellular mechanisms which drive tumor initiation, main- exome-wide mutation analysis by sanger-sequencing to tenance and progression of cancers. Characterization of demonstrate the genomic profile of CRC, which included genomes by next-generation sequencing (NGS) has per- high-frequency mutated genes such as APC, KRA, TP53.2,3 mitted significant advances in gastrointestinal cancer With the development of NGS, The Cancer Genome Atlas care. These discoveries have fueled the development of (TCGA) network further expanded the genome profile. They novel therapeutics and have laid the groundwork for the demonstrated 32 somatic recurrently mutated genes, among development of new treatment strategies. Work in col- the somatic mutations identified in 24 genes. The most orectal cancer (CRC) has been in the forefront of these frequent mutated genes were APC, TP53, KRAS, PIK3CA, advances. With the continued development of NGS FBXW7, SMAD4, TCF/L2, NRAS, ACVR2A, APC, TGFBR2, technology and the positive clinical experience in CRC, MSH3, MSH6, SLC9A9, TCF7L2 and BRAF V600E were noted.4 genome work has begun in esophagogastric, pancreatic, At the current time, there are previously identified genes, and hepatocellular carcinomas as well. which are directing clinical treatment options or are used as KEYWORDS: Tumor profiling, colorectal carcinoma, prognostic indicators (see Table 1): esophagogastric carcinoma, pancreatic carcinoma, hepatocellular carcinoma Table 1.
    [Show full text]
  • The Mtor Substrate S6 Kinase 1 (S6K1)
    The Journal of Neuroscience, July 26, 2017 • 37(30):7079–7095 • 7079 Cellular/Molecular The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury X Hassan Al-Ali,1,2,3* Ying Ding,5,6* Tatiana Slepak,1* XWei Wu,5 Yan Sun,5,7 Yania Martinez,1 Xiao-Ming Xu,5 Vance P. Lemmon,1,3 and XJohn L. Bixby1,3,4 1Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida 33136, 2Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, Florida 33136, 3Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136, 4Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida 33136, 5Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, 6Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China, and 7Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China Themammaliantargetofrapamycin(mTOR)positivelyregulatesaxongrowthinthemammaliancentralnervoussystem(CNS).Althoughaxon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR’s positive effect on axon growth. In contrast to this expectation, we demon- strate that inhibition of S6K1 in CNS neurons promotes neurite outgrowth in vitro by twofold to threefold.
    [Show full text]
  • The Mtor Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury
    This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Cellular/Molecular The mTOR substrate S6 Kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for Central Nervous System injury Hassan Al-Ali1,2,3, Ying Ding5,6, Tatiana Slepak1, Wei Wu5, Yan Sun5,7, Yania Martinez1, Xiao-Ming Xu5, V.P. Lemmon1,3 and J.l. Bixby1,3,4 1The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA. 2Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. 3Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA. 4Department of Molecular & Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. 5Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA. 6Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China. 7Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. DOI: 10.1523/JNEUROSCI.0931-17.2017 Received: 4 April 2017 Revised: 18 May 2017 Accepted: 27 May 2017 Published: 16 June 2017 Author contributions: H.A.-A., Y.D., T.S., W.W., Y.S., X.-M.X., V.P.L., and J.B. designed research; H.A.-A., Y.D., T.S., W.W., Y.S., and Y.M.
    [Show full text]
  • CENTOGENE's Severe and Early Onset Disorder Gene List
    CENTOGENE’s severe and early onset disorder gene list USED IN PRENATAL WES ANALYSIS AND IDENTIFICATION OF “PATHOGENIC” AND “LIKELY PATHOGENIC” CENTOMD® VARIANTS IN NGS PRODUCTS The following gene list shows all genes assessed in prenatal WES tests or analysed for P/LP CentoMD® variants in NGS products after April 1st, 2020. For searching a single gene coverage, just use the search on www.centoportal.com AAAS, AARS1, AARS2, ABAT, ABCA12, ABCA3, ABCB11, ABCB4, ABCB7, ABCC6, ABCC8, ABCC9, ABCD1, ABCD4, ABHD12, ABHD5, ACACA, ACAD9, ACADM, ACADS, ACADVL, ACAN, ACAT1, ACE, ACO2, ACOX1, ACP5, ACSL4, ACTA1, ACTA2, ACTB, ACTG1, ACTL6B, ACTN2, ACVR2B, ACVRL1, ACY1, ADA, ADAM17, ADAMTS2, ADAMTSL2, ADAR, ADARB1, ADAT3, ADCY5, ADGRG1, ADGRG6, ADGRV1, ADK, ADNP, ADPRHL2, ADSL, AFF2, AFG3L2, AGA, AGK, AGL, AGPAT2, AGPS, AGRN, AGT, AGTPBP1, AGTR1, AGXT, AHCY, AHDC1, AHI1, AIFM1, AIMP1, AIPL1, AIRE, AK2, AKR1D1, AKT1, AKT2, AKT3, ALAD, ALDH18A1, ALDH1A3, ALDH3A2, ALDH4A1, ALDH5A1, ALDH6A1, ALDH7A1, ALDOA, ALDOB, ALG1, ALG11, ALG12, ALG13, ALG14, ALG2, ALG3, ALG6, ALG8, ALG9, ALMS1, ALOX12B, ALPL, ALS2, ALX3, ALX4, AMACR, AMER1, AMN, AMPD1, AMPD2, AMT, ANK2, ANK3, ANKH, ANKRD11, ANKS6, ANO10, ANO5, ANOS1, ANTXR1, ANTXR2, AP1B1, AP1S1, AP1S2, AP3B1, AP3B2, AP4B1, AP4E1, AP4M1, AP4S1, APC2, APTX, AR, ARCN1, ARFGEF2, ARG1, ARHGAP31, ARHGDIA, ARHGEF9, ARID1A, ARID1B, ARID2, ARL13B, ARL3, ARL6, ARL6IP1, ARMC4, ARMC9, ARSA, ARSB, ARSL, ARV1, ARX, ASAH1, ASCC1, ASH1L, ASL, ASNS, ASPA, ASPH, ASPM, ASS1, ASXL1, ASXL2, ASXL3, ATAD3A, ATCAY, ATIC, ATL1, ATM, ATOH7,
    [Show full text]
  • Mapping the Mammalian Ribosome Quality Control Complex Interactome Using Proximity Labeling Approaches
    M BoC | ARTICLE Mapping the mammalian ribosome quality control complex interactome using proximity labeling approaches Nathan Zuzow, Arit Ghosh, Marilyn Leonard, Jeffrey Liao, Bing Yang, and Eric J. Bennett* Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093 ABSTRACT Previous genetic and biochemical studies from Saccharomyces cerevisiae have Monitoring Editor identified a critical ribosome-associated quality control complex (RQC) that facilitates resolu- Sandra Wolin tion of stalled ribosomal complexes. While components of the mammalian RQC have been National Cancer Institute, NIH examined in vitro, a systematic characterization of RQC protein interactions in mammalian Received: Dec 12, 2017 cells has yet to be described. Here we utilize both proximity-labeling proteomic approaches, Revised: Mar 6, 2018 BioID and APEX, and traditional affinity-based strategies to both identify interacting proteins Accepted: Mar 9, 2018 of mammalian RQC members and putative substrates for the RQC resident E3 ligase, Ltn1. Surprisingly, validation studies revealed that a subset of substrates are ubiquitylated by Ltn1 in a regulatory manner that does not result in subsequent substrate degradation. We demon- strate that Ltn1 catalyzes the regulatory ubiquitylation of ribosomal protein S6 kinase 1 and 2 (RPS6KA1, RPS6KA3). Further, loss of Ltn1 function results in hyperactivation of RSK1/2 signaling without impacting RSK1/2 protein turnover. These results suggest that Ltn1-medi- ated RSK1/2 ubiquitylation is inhibitory and establishes a new role for Ltn1 in regulating mi- togen-activated kinase signaling via regulatory RSK1/2 ubiquitylation. Taken together, our results suggest that mammalian RQC interactions are difficult to observe and may be more transient than the homologous complex in S.
    [Show full text]