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Elspeth A Bruford - One of the best experts on this subject based on the ideXlab platform.

  • HUGO Gene Nomenclature committee hgnc recommendations for the designation of Gene fusions
    Leukemia, 2021
    Co-Authors: Elspeth A Bruford, Cristina R Antonescu, Andrew J Carroll, Arul M Chinnaiyan, Ian A Cree, Nicholas C P Cross, Raymond Dalgleish, Robert Peter Gale
    Abstract:

    Gene fusions have been discussed in the scientific literature since they were first detected in cancer cells in the early 1980s. There is currently no standardized way to denote the Genes involved in fusions, but in the majority of publications the Gene symbols in question are listed either separated by a hyphen (-) or by a forward slash (/). Both types of designation suffer from important shortcomings. HGNC has worked with the scientific community to determine a new, instantly recognizable and unique separator—a double colon (::)—to be used in the description of fusion Genes, and advocates its usage in all databases and articles describing Gene fusions.

  • Guidelines for human Gene Nomenclature
    Nature Genetics, 2020
    Co-Authors: Elspeth A Bruford, Bryony Braschi, Paul Denny, Tamsin E. M. Jones, Ruth L. Seal, Susan Tweedie
    Abstract:

    Standardized Gene naming is crucial for effective communication about Genes, and as genomics becomes increasingly important in health care, the need for a consistent language to refer to human Genes becomes ever more essential. Here, we present the current HUGO Gene Nomenclature Committee (HGNC) guidelines for naming not only protein-coding Genes but also RNA Genes and pseudoGenes, and we outline the changes in approach and ethos that have resulted from the discoveries of the past few decades.

  • correction to the official unified Nomenclature adopted by the hgnc calls for the use of the acronyms ccn1 6 and discontinuation in the use of cyr61 ctgf nov and wisp 1 3 respectively
    Journal of Cell Communication and Signaling, 2018
    Co-Authors: Bernard Perbal, Susan Tweedie, Elspeth A Bruford
    Abstract:

    An examination of the confusion Generated around the use of different acronyms for CCN proteins has been performed by the editors of the HUGO Gene Nomenclature Committee upon the request of the International CCN Society Scientific Committee. After careful consideration of the various arguments, and after polling the community of researchers who have published in the field over the past ten years, the HGNC have decided to adopt and approve the CCN Nomenclature for all 6 Genes. Effective October 2018, the Genes referred to as CYR61, CTGF, NOV and WISP1–3 will be respectively designated by the Gene symbols CCN1–6 with corresponding Gene names « cellular communication Q2 network factor 1–6 ». We believe that this decision will be a step towards better communication between researchers working in the field, and will set the stage for fruitful collaborative projects. Accordingly, the Journal of Cell Communication and Signaling, the official journal of the International CCN Society, available both in print and online, constitutes a unique window into the CCN field. This official Nomenclature will benefit the international scientific community that is supported by the established and renowned professionalism of the Springer-Nature publishing group.

  • selenoprotein Gene Nomenclature
    Journal of Biological Chemistry, 2016
    Co-Authors: Raymond F. Burk, Brigelius Flohe Regina, Sergi Castellano, Elspeth A Bruford, Elias S J Arner, Bradley A. Carlson, Marla J Berry, Laurent Chavatte
    Abstract:

    Abstract The human genome contains 25 Genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4 and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine-R-sulfoxide reductase 1) and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved Nomenclature for several other Genes. Therefore, there is a need to implement a rational and coherent Nomenclature system for selenoprotein-encoding Genes. Our solution is to use the root symbol SELENO followed by a letter. This Nomenclature applies to SELENOF (selenoprotein F, the 15 kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV) and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing and ambiguous designations for selenoprotein Genes and is applicable to selenoproteins across vertebrates.

  • selenoprotein Gene Nomenclature
    Journal of Biological Chemistry, 2016
    Co-Authors: Raymond F. Burk, Brigelius Flohe Regina, Sergi Castellano, Elspeth A Bruford, Elias S J Arner, Bradley A. Carlson, Marla J Berry, Laurent Chavatte
    Abstract:

    Abstract The human genome contains 25 Genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4 and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine-R-sulfoxide reductase 1) and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved Nomenclature for several other Genes. Therefore, there is a need to implement a rational and coherent Nomenclature system for selenoprotein-encoding Genes. Our solution is to use the root symbol SELENO followed by a letter. This Nomenclature applies to SELENOF (selenoprotein F, the 15 kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV) and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing and ambiguous designations for selenoprotein Genes and is applicable to selenoproteins across vertebrates.

Mathew W Wright - One of the best experts on this subject based on the ideXlab platform.

  • A review of the new HGNC Gene family resource
    Human Genomics, 2016
    Co-Authors: Kristian A Gray, Ruth L. Seal, Mathew W Wright, Susan Tweedie, Elspeth A Bruford
    Abstract:

    The HUGO Gene Nomenclature Committee (HGNC) approves unique Gene symbols and names for human loci. As well as naming genomic loci, we manually curate Genes into family sets based on shared characteristics such as function, homology or phenotype. Each HGNC Gene family has its own dedicated Gene family report on our website, www.Genenames.org . We have recently redesigned these reports to support the visualisation and browsing of complex relationships between families and to provide extra curated information such as family descriptions, protein domain graphics and Gene family aliases. Here, we review how our Gene families are curated and explain how to view, search and download the Gene family data.

  • a short guide to long non coding rna Gene Nomenclature
    Human Genomics, 2014
    Co-Authors: Mathew W Wright
    Abstract:

    The HUGO Gene Nomenclature Committee (HGNC) is the only organisation authorised to assign standardised Nomenclature to human Genes. Of the 38,000 approved Gene symbols in our database (http://www.Genenames.org), the majority represent protein-coding (pc) Genes; however, we also name pseudoGenes, phenotypic loci, some genomic features, and to date have named more than 8,500 human non-protein coding RNA (ncRNA) Genes and ncRNA pseudoGenes. We have already established unique names for most of the small ncRNA Genes by working with experts for each class. Small ncRNAs can be defined into their respective classes by their shared homology and common function. In contrast, long non-coding RNA (lncRNA) Genes represent a disparate set of loci related only by their size, more than 200 bases in length, share no conserved sequence homology, and have variable functions. As with pc Genes, wherever possible, lncRNAs are named based on the known function of their product; a short guide is presented herein to help authors when developing novel Gene symbols for lncRNAs with characterised function. Researchers must contact the HGNC with their suggestions prior to publication, to check whether the proposed Gene symbol can be approved. Although thousands of lncRNAs have been predicted in the human genome, for the vast majority their function remains unresolved. lncRNA Genes with no known function are named based on their genomic context. Working with lncRNA researchers, the HGNC aims to provide unique and, wherever possible, meaningful Gene symbols to all lncRNA Genes.

  • Gene family matters: expanding the HGNC resource
    Human Genomics, 2012
    Co-Authors: Louise C Daugherty, Ruth L. Seal, Mathew W Wright, Elspeth A Bruford
    Abstract:

    The HUGO Gene Nomenclature Committee (HGNC) assigns approved Gene symbols to human loci. There are currently over 33,000 approved Gene symbols, the majority of which represent protein-coding Genes, but we also name other locus types such as non-coding RNAs, pseudoGenes and phenotypic loci. Where relevant, the HGNC organise these Genes into Gene families and groups. The HGNC website http://www.Genenames.org/ is an online repository of HGNC-approved Gene Nomenclature and associated resources for human Genes, and includes links to genomic, proteomic and phenotypic information. In addition to this, we also have dedicated Gene family web pages and are currently expanding and Generating more of these pages using data curated by the HGNC and from information derived from external resources that focus on particular Gene families. Here, we review our current online resources with a particular focus on our Gene family data, using it to highlight our new Gene Symbol Report and Gene family data downloads.

  • Naming 'junk': Human non-protein coding RNA (ncRNA) Gene Nomenclature
    Human Genomics, 2011
    Co-Authors: Mathew W Wright, Elspeth A Bruford
    Abstract:

    Previously, the majority of the human genome was thought to be 'junk' DNA with no functional purpose. Over the past decade, the field of RNA research has rapidly expanded, with a concomitant increase in the number of non-protein coding RNA (ncRNA) Genes identified in this 'junk'. Many of the encoded ncRNAs have already been shown to be essential for a variety of vital functions, and this wealth of annotated human ncRNAs requires standardised naming in order to aid effective communication. The HUGO Gene Nomenclature Committee (HGNC) is the only organisation authorised to assign standardised Nomenclature to human Genes. Of the 30,000 approved Gene symbols currently listed in the HGNC database ( http://www.Genenames.org/search ), the majority represent protein-coding Genes; however, they also include pseudoGenes, phenotypic loci and some genomic features. In recent years the list has also increased to include almost 3,000 named human ncRNA Genes. HGNC is actively engaging with the RNA research community in order to provide unique symbols and names for each sequence that encodes an ncRNA. Most of the classical small ncRNA Genes have now been provided with a unique Nomenclature, and work on naming the long (> 200 nucleotides) non-coding RNAs (lncRNAs) is ongoing.

  • Naming “junk”: human nonprotein coding RNA (ncRNA) Gene Nomenclature
    2011
    Co-Authors: Mathew W Wright, Elspeth A Bruford
    Abstract:

    Previously, the majority of the human genome was thought to be ‘junk ’ DNA with no functional purpose. Over the past decade, the field of RNA research has rapidly expanded, with a concomitant increase in the number of non-protein coding RNA (ncRNA) Genes identified in this ‘junk’. Many of the encoded ncRNAs have already been shown to be essential for a variety of vital functions, and this wealth of annotated human ncRNAs requires stan-dardised naming in order to aid effective communication. The HUGO Gene Nomenclature Committee (HGNC) is the only organisation authorised to assign standardised Nomenclature to human Genes. Of the 30,000 approved Gene symbols currently listed in the HGNC databas

Sudheer Giddaluru - One of the best experts on this subject based on the ideXlab platform.

  • Overview of occipital cortex enriched Genes analysed in this study.
    2012
    Co-Authors: Kari M. Ersland, Andrea Christoforou, Christine Stansberg, Thomas Espeseth, Manuel Mattheisen, Morten Mattingsdal, Gudmundur A. Hardarson, Thomas Hansen, Carla P. D. Fernandes, Sudheer Giddaluru
    Abstract:

    The 11 occipital cortex enriched Genes [29] were used as candidates to search for association to nine test measures of cognitive functions [37]–[40], at the single Gene- and Gene set-based level. The HUGO Gene Nomenclature Committee (HGNC) symbol, Ensembl Genome Browser (release 54) identification [33] and Gene description is shown.

  • Overview of frontomedial cortex enriched Genes analysed in this study.
    2012
    Co-Authors: Kari M. Ersland, Andrea Christoforou, Christine Stansberg, Thomas Espeseth, Manuel Mattheisen, Morten Mattingsdal, Gudmundur A. Hardarson, Thomas Hansen, Carla P. D. Fernandes, Sudheer Giddaluru
    Abstract:

    The 29 frontomedial enriched cortical Genes [29] were used as candidates to search for association to nine test measures of cognitive functions [37]–[40], at the single Gene- and Gene set-based level. The HUGO Gene Nomenclature Committee (HGNC) symbol, Ensembl Genome Browser (release 54) identification [33] and Gene description is shown.

  • Overview of temporal cortex enriched Genes analysed in this study.
    2012
    Co-Authors: Kari M. Ersland, Andrea Christoforou, Christine Stansberg, Thomas Espeseth, Manuel Mattheisen, Morten Mattingsdal, Gudmundur A. Hardarson, Thomas Hansen, Carla P. D. Fernandes, Sudheer Giddaluru
    Abstract:

    The 22 temporal cortex enriched Genes [29] were used as candidates to search for association to nine test measures of cognitive functions [37]–[40], at the single Gene- and Gene set-based level. The HUGO Gene Nomenclature Committee (HGNC) symbol, Ensembl Genome Browser (release 54) identification [33] and Gene description is shown.

  • Gene-based analysis of temporal cortex enriched Genes for association to cognitive abilities.
    2012
    Co-Authors: Kari M. Ersland, Andrea Christoforou, Christine Stansberg, Thomas Espeseth, Manuel Mattheisen, Morten Mattingsdal, Gudmundur A. Hardarson, Thomas Hansen, Carla P. D. Fernandes, Sudheer Giddaluru
    Abstract:

    The temporal cortex enriched Genes (n = 22) were analysed for allelic association to nine test measures from the NCNG GWAS. For trait abbreviations see Table 4. Modified Sidak's minimum P-value for each candidate Gene was extracted [45], and only modified Sidak's P-values0.05), HGNC: HUGO Gene Nomenclature Committee, SNPs: number of SNPs assigned to each Gene by LDsnpR.

  • Gene-based analysis of occipital cortex enriched Genes for association to cognitive abilities.
    2012
    Co-Authors: Kari M. Ersland, Andrea Christoforou, Christine Stansberg, Thomas Espeseth, Manuel Mattheisen, Morten Mattingsdal, Gudmundur A. Hardarson, Thomas Hansen, Carla P. D. Fernandes, Sudheer Giddaluru
    Abstract:

    The occipital cortex enriched Genes (n = 11) were analysed for allelic association to nine test measures from the NCNG GWAS. For trait abbreviations see Table 4. Modified Sidak's minimum P-value for each candidate Gene was extracted [45], and only modified Sidak's P-values0.05), HGNC: HUGO Gene Nomenclature Committee, SNPs: number of SNPs assigned to each Gene by LDsnpR.

Sue Povey - One of the best experts on this subject based on the ideXlab platform.

  • Genew: the Human Gene Nomenclature Database, 2004 updates
    Nucleic Acids Research, 2004
    Co-Authors: Hester Wain, Michael J Lush, Fabrice Ducluzeau, Varsha K. Khodiyar, Sue Povey
    Abstract:

    Genew, the Human Gene Nomenclature Database http://www.Gene.ucl.ac.uk/cgi-bin/Nomenclature/searchGenes.pl is the only resource that provides data for all human Genes that have approved symbols. It is managed by the HUGO Gene Nomenclature Committee (HGNC) as a confidential database, containing over 22 000 records, 75% of which are represented online by a publicly searchable text file. Since 2002, there have been significant improvements to the Genew search engine. Additionally we have increased our capacity to analyse confidential sequence data, which has enabled us to manage the large numbers of Gene symbol requests that we receive from the chromosome sequencing consortia.

  • ABSTRACT
    2003
    Co-Authors: Hester M. Wain, Michael J Lush, Sue Povey, Fabrice Ducluzeau, Varsha K. Khodiyar, The Human Gene Nomenclature Database
    Abstract:

    searchGenes.pl is the only resource that provides data for all human Genes that have approved symbols. It is managed by the HUGO Gene Nomenclature Committee (HGNC) as a con®dential database, containing over 22 000 records, 75 % of which are represented online by a publicly searchable text ®le. Since 2002, there have been signi®cant improvements to the Genew search engine. Additionally we have increased our capacity to analyse con®dential sequence data, which has enabled us to manage the large numbers of Gene symbol requests that we receive from the chromosome sequencing consortia. OVERVIEW The Genew database (1) is the primary resource for approved Gene symbols for all other human Genetic databases. We exchange information with many databases and organizations throughout the world to update new Gene symbols and encourage their use. IMPROVEMENTS SINCE 2002 New search engine The new version of the Genew search engine was made available in 2002. This can be found at the sam

  • Genew: the Human Gene Nomenclature Database
    Nucleic acids research, 2002
    Co-Authors: Hester Wain, Michael J Lush, Fabrice Ducluzeau, Sue Povey
    Abstract:

    Genew, the Human Gene Nomenclature Database, is the only resource that provides data for all human Genes which have approved symbols. It is managed by the HUGO Gene Nomenclature Committee (HGNC) as a confidential database, containing over 16 000 records, 80% of which are represented on the Web by searchable text files. The data in Genew are highly curated by HGNC editors and Gene records can be searched on the Web by symbol or name to directly retrieve information on Gene symbol, Gene name, cytoGenetic location, OMIM number and PubMed ID. Data are integrated with other human Gene databases, e.g. GDB, LocusLink and SWISS-PROT, and approved Gene symbols are carefully co-ordinated with the Mouse Genome Database (MGD). Approved Gene symbols are available for querying and browsing at http://www.Gene.ucl.ac.uk/cgi-bin/Nomenclature/ searchGenes.pl.

Casas Terradellas Eduard - One of the best experts on this subject based on the ideXlab platform.

  • Paper de la proteïna HERC1 en la via de senyalització de mTOR. Erk i p38 reguladors de la senyalització per aminoàcids
    'Edicions de la Universitat de Barcelona', 2009
    Co-Authors: Casas Terradellas Eduard
    Abstract:

    D'acord amb el comitè de nomenclatura gènica (HGNC) de l'organització del genoma humà (HUGO), es defineix com a proteïna HERC tota aquella proteïna que conté com a mínim i de forma conjunta un domini HECT i un domini RCC1 like (RLD) en la seva seqüència. En l'actualitat s'han identificat 6 membres per aquesta família de proteïnes d'entre les quals la proteïna HERC1 és la primera que es va identificar i el membre fundador de la família. La identificació d'aquesta proteïna va tenir lloc mitjançant la búsqueda de seqüències oncogèniques humanes a partir de cèl·lules de càncer de mama, i tot i que s'ha observat la seva sobrexpressió en diferents càncers, i que s'ha descrit la seva interacció amb difererents proteïnes involucrades amb processos de tràfic de membrana, a dia d'avui no es coneix encara quina es la seva funció fisiològica. L'objectiu principal d'aquesta tesi ha estat l'estudi del paper de la proteïna HERC1 en la via de senyalització de mTOR. Amb l'objectiu de facilitar aquest estudi vàrem idear en primer lloc un sistema per a l'estudi de proteïnes gegants per PAGE/SDS que al mateix temps ens permetés l'anàlisi de proteïnes amb pesos moleculars menors en un sol gel. Aquest sistema el vàrem anomenar LAG gel (Low Acrylamide Gradient gel), i consisteix en un gel que combina de forma contínua un gel de poliacrilamida de baix percentatge d'acrilamida (4%) i una proporció menor de l'habitual d'acrilamida:bisacrilamida (80:1) (que permet l'entrada de les proteïnes gegants al gel) amb un gel en gradient del 6 al 15% amb una proporció acrilamida/bisacrilamida de 40:1. Hem comprobat que aquest sistema permet separar proteïnes des de 5 KDa fins a proteïnes gegants en únic gel, amb els avantatges que això comporta pel que fa al estalvi de temps i de reactius. A l'any 2006, en col·laboració amb el nostre laboratori, es va descriure que HERC1 interacciona amb la tuberina (TSC2), una proteïna que juntament amb l'hamarina (TSC1) forma el complex de l'esclerosi tuberosa (TSC). Aquest complex actua com a regulador negatiu de la via de senyalització de mTOR, estimulant l'activitat GTPasa de Rheb a través del domini GAP de TSC2. En aquest treball hem comprovat que HERC1 s'associa als dos components de l'esclerosi tuberosa (tuberina i hamartina) estabilitzant aquest complex. A més a més, hem observat com aquesta interacció té lloc en menor grau amb els mutants de TSC2 identificats en pacients d'esclerosi tuberosa R611Q i R905Q, és independent de la inhibició de la via de señalización de mTOR induïda por dejuni o de la seva activació mitjançant aminoàcids o insulina. En canvi, tot i aquestes interaccions, HERC1 no sembla participar en la fosforilació de proteïnes involucrades en la via de mTOR com les p70 S6K, 4EBP1, Akt o S6, ni tampoc en la regulació del procés de l'autofàgia. En canvi, si que afecta a un altre procés mTOR dependent com és la biogénesi de ribosomes. En aquest sentit hem pogut comprovar mitjançant experiments de silenciació del gen d'HERC1 que la disminució dels nivells d'HERC1 provoca disminucions significatives dels nivells d'ADN ribosomal 18S així com de l'actividad del promotor d'aquest gen.La realització d'experiments d'activació amb aminoàcids per a l'estudi del paper de la proteïna HERC1 en la via de senyalització de mTOR ens va permetre observar que el tractament amb aminoàcids indueix la fosforilació de una proteïna de 80-90 KDa, però no de la isoforma p70 de la S6K1. Aquesta observació ens va portar a l'estudi de l'activació de la p70 S6K1 en resposta a aminoàcids, observant que en respuesta a aquests nutrients es produeix l'activació de les proteïnes quinasa activades por MAPKs (MKs), RSK y MSK. A més a més, hem vist que l'activació d'ambdues quinases té lloc en resposta a la activació de les MAPKs, Erk o p38, a través d'un mecanisme compensatori en el qual quan la Erk es troba inhibida, l'activació de la RSK i MSK té lloc a través de p38 i viceversa.According to the Human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC), HERC proteins are defined as those proteins containing both RLD and HECT domains in their amino acid sequence. Currently, six HERC proteins have been identified. The physiological role of HERC1, the founding member of the family, still remains to be clarified. The main objective for this thesis has been the study of HERC1 role in the mTOR signalling pathway. First, we created a new system to study giant and smaller proteins by means of PAGE/SDS in a unique gel. We called it LAG gel (Low Acrylamide Gradient gel) and is formed by the combination of a low percentage acrylamide gel (4% and a ratio Acrylamide/Bisacrylamide 80:1) and a gradient gel (6-15%, A/B 80:1). This system permits to analyze simultaneously giant and smaller proteins in a unique gel obtaining good separation ressolutions for all proteins and to save time and reactants. It's been described that HERC1 is able to interact with TSC2 (tuberin), a protein which together with TSC1 (hamartin) constitutes the tuberous sclerosis complex (TSC). This complex acts as a negative regulator of the mTOR signalling pathway through the stimulation of Rheb GTPase activity by TSC2 GAP domain. We have proved that HERC1 interacts with both TSC members (tuberin and hamartin) stabilizing it. Furthermore, we have observed that this interaction is lower with TSC2 mutants identified from tuberous sclerosis patients, R611Q and R905Q and is independent of mTOR signalling pathway inhibition by starving or activation by aminoacids or insulin. Despite these interactions, HERC1 isn't involved in the phosphorylation of some mTOR signalling pathway proteins such as p70 S6K, 4EBP1, Akt, S6, nor in the regulation of Autophagy. However, HERC1 is involved in the mTOR dependent process of ribosome bioGenesis. We have proved that the HERC1 Gene knock down causes a significant decrease of the 18S ribosomal DNA as well as a reduction of the activity of the promoter of this Gene.The performance of activation assays with aminoacids in the study of the HERC1 role in the mTOR signalling pathway permitted us to observe that this cell treatment induce the phosphorylation of a 90 KDa protein and a 110 KDa protein, but not the p70 isoform of S6K1. We have seen that these 90 and 110 KDa bands correspond to the kinases activated by MAPKs (MKs), RSK and MSK. Furthermore, we have proved that the activation of both kinases takes place in response of the activation of the MAPKs, Erk or p38 through a compensatory mechanish in which when Erk is not active, the RSK and MSK activation is induced by p38 and viceversa.

  • Paper de la proteïna HERC1 en la via de senyalització de mTOR. Erk i p38 reguladors de la senyalització per aminoàcids
    'Edicions de la Universitat de Barcelona', 2009
    Co-Authors: Casas Terradellas Eduard
    Abstract:

    [cat] D'acord amb el comitè de nomenclatura gènica (HGNC) de l'organització del genoma humà (HUGO), es defineix com a proteïna HERC tota aquella proteïna que conté com a mínim i de forma conjunta un domini HECT i un domini RCC1 like (RLD) en la seva seqüència. En l'actualitat s'han identificat 6 membres per aquesta família de proteïnes d'entre les quals la proteïna HERC1 és la primera que es va identificar i el membre fundador de la família. La identificació d'aquesta proteïna va tenir lloc mitjançant la búsqueda de seqüències oncogèniques humanes a partir de cèl·lules de càncer de mama, i tot i que s'ha observat la seva sobrexpressió en diferents càncers, i que s'ha descrit la seva interacció amb difererents proteïnes involucrades amb processos de tràfic de membrana, a dia d'avui no es coneix encara quina es la seva funció fisiològica. L'objectiu principal d'aquesta tesi ha estat l'estudi del paper de la proteïna HERC1 en la via de senyalització de mTOR. Amb l'objectiu de facilitar aquest estudi vàrem idear en primer lloc un sistema per a l'estudi de proteïnes gegants per PAGE/SDS que al mateix temps ens permetés l'anàlisi de proteïnes amb pesos moleculars menors en un sol gel. Aquest sistema el vàrem anomenar LAG gel (Low Acrylamide Gradient gel), i consisteix en un gel que combina de forma contínua un gel de poliacrilamida de baix percentatge d'acrilamida (4%) i una proporció menor de l'habitual d'acrilamida:bisacrilamida (80:1) (que permet l'entrada de les proteïnes gegants al gel) amb un gel en gradient del 6 al 15% amb una proporció acrilamida/bisacrilamida de 40:1. Hem comprobat que aquest sistema permet separar proteïnes des de 5 KDa fins a proteïnes gegants en únic gel, amb els avantatges que això comporta pel que fa al estalvi de temps i de reactius. A l'any 2006, en col·laboració amb el nostre laboratori, es va descriure que HERC1 interacciona amb la tuberina (TSC2), una proteïna que juntament amb l'hamarina (TSC1) forma el complex de l'esclerosi tuberosa (TSC). Aquest complex actua com a regulador negatiu de la via de senyalització de mTOR, estimulant l'activitat GTPasa de Rheb a través del domini GAP de TSC2. En aquest treball hem comprovat que HERC1 s'associa als dos components de l'esclerosi tuberosa (tuberina i hamartina) estabilitzant aquest complex. A més a més, hem observat com aquesta interacció té lloc en menor grau amb els mutants de TSC2 identificats en pacients d'esclerosi tuberosa R611Q i R905Q, és independent de la inhibició de la via de señalización de mTOR induïda por dejuni o de la seva activació mitjançant aminoàcids o insulina. En canvi, tot i aquestes interaccions, HERC1 no sembla participar en la fosforilació de proteïnes involucrades en la via de mTOR com les p70 S6K, 4EBP1, Akt o S6, ni tampoc en la regulació del procés de l'autofàgia. En canvi, si que afecta a un altre procés mTOR dependent com és la biogénesi de ribosomes. En aquest sentit hem pogut comprovar mitjançant experiments de silenciació del gen d'HERC1 que la disminució dels nivells d'HERC1 provoca disminucions significatives dels nivells d'ADN ribosomal 18S així com de l'actividad del promotor d'aquest gen. La realització d'experiments d'activació amb aminoàcids per a l'estudi del paper de la proteïna HERC1 en la via de senyalització de mTOR ens va permetre observar que el tractament amb aminoàcids indueix la fosforilació de una proteïna de 80-90 KDa, però no de la isoforma p70 de la S6K1. Aquesta observació ens va portar a l'estudi de l'activació de la p70 S6K1 en resposta a aminoàcids, observant que en respuesta a aquests nutrients es produeix l'activació de les proteïnes quinasa activades por MAPKs (MKs), RSK y MSK. A més a més, hem vist que l'activació d'ambdues quinases té lloc en resposta a la activació de les MAPKs, Erk o p38, a través d'un mecanisme compensatori en el qual quan la Erk es troba inhibida, l'activació de la RSK i MSK té lloc a través de p38 i viceversa.[eng] According to the Human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC), HERC proteins are defined as those proteins containing both RLD and HECT domains in their amino acid sequence. Currently, six HERC proteins have been identified. The physiological role of HERC1, the founding member of the family, still remains to be clarified. The main objective for this thesis has been the study of HERC1 role in the mTOR signalling pathway. First, we created a new system to study giant and smaller proteins by means of PAGE/SDS in a unique gel. We called it LAG gel (Low Acrylamide Gradient gel) and is formed by the combination of a low percentage acrylamide gel (4% and a ratio Acrylamide/Bisacrylamide 80:1) and a gradient gel (6-15%, A/B 80:1). This system permits to analyze simultaneously giant and smaller proteins in a unique gel obtaining good separation ressolutions for all proteins and to save time and reactants. It's been described that HERC1 is able to interact with TSC2 (tuberin), a protein which together with TSC1 (hamartin) constitutes the tuberous sclerosis complex (TSC). This complex acts as a negative regulator of the mTOR signalling pathway through the stimulation of Rheb GTPase activity by TSC2 GAP domain. We have proved that HERC1 interacts with both TSC members (tuberin and hamartin) stabilizing it. Furthermore, we have observed that this interaction is lower with TSC2 mutants identified from tuberous sclerosis patients, R611Q and R905Q and is independent of mTOR signalling pathway inhibition by starving or activation by aminoacids or insulin. Despite these interactions, HERC1 isn't involved in the phosphorylation of some mTOR signalling pathway proteins such as p70 S6K, 4EBP1, Akt, S6, nor in the regulation of Autophagy. However, HERC1 is involved in the mTOR dependent process of ribosome bioGenesis. We have proved that the HERC1 Gene knock down causes a significant decrease of the 18S ribosomal DNA as well as a reduction of the activity of the promoter of this Gene. The performance of activation assays with aminoacids in the study of the HERC1 role in the mTOR signalling pathway permitted us to observe that this cell treatment induce the phosphorylation of a 90 KDa protein and a 110 KDa protein, but not the p70 isoform of S6K1. We have seen that these 90 and 110 KDa bands correspond to the kinases activated by MAPKs (MKs), RSK and MSK. Furthermore, we have proved that the activation of both kinases takes place in response of the activation of the MAPKs, Erk or p38 through a compensatory mechanish in which when Erk is not active, the RSK and MSK activation is induced by p38 and viceversa