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1.
Nat Immunol ; 12(4): 352-61, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21399638

RESUMEN

Here we report an unbiased analysis of the cytotoxic T lymphocyte (CTL) serine-threonine phosphoproteome by high-resolution mass spectrometry. We identified approximately 2,000 phosphorylations in CTLs, of which approximately 450 were controlled by T cell antigen receptor (TCR) signaling. A significantly overrepresented group of molecules identified included transcription activators, corepressors and chromatin regulators. A focus on chromatin regulators showed that CTLs had high expression of the histone deacetylase HDAC7 but continually phosphorylated and exported this transcriptional repressor from the nucleus. Dephosphorylation of HDAC7 resulted in its accumulation in the nucleus and suppressed expression of genes encoding key cytokines, cytokine receptors and adhesion molecules that determine CTL function. Screening of the CTL phosphoproteome has thus identified intrinsic pathways of serine-threonine phosphorylation that target chromatin regulators and determine the CTL functional program.


Asunto(s)
Histona Desacetilasas/metabolismo , Fosfoproteínas/metabolismo , Proteómica/métodos , Transducción de Señal , Linfocitos T Citotóxicos/metabolismo , Secuencia de Aminoácidos , Animales , Núcleo Celular/metabolismo , Células Cultivadas , Cromatografía Liquida , Citosol/metabolismo , Femenino , Perfilación de la Expresión Génica , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Histona Desacetilasas/genética , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Confocal , Datos de Secuencia Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosfoproteínas/genética , Fosforilación , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T Citotóxicos/citología
3.
Eur J Hum Genet ; 15(5): 528-32, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17356548

RESUMEN

Although biobanks are vital for modern medical research, serious concerns have been raised about the legal basis and framework of such endeavours. This led the German 'Telematics Platform for Medical Research Networks' ('Telematikplattform für Medizinische Forschungsnetze', TMF) to initiate a project in 2004 that was designed to place German biobanks on a sound legal footing. This project involved the planning, writing and evaluation of an expert report that addresses in great detail the legal issues concerning property rights, medical professional regulations, general liability insurance, resource continuity and research secrecy. Here, we provide a brief summary of the major results of this project.


Asunto(s)
Bancos de Muestras Biológicas/ética , Bancos de Muestras Biológicas/legislación & jurisprudencia , Bancos de Muestras Biológicas/normas , Alemania , Guías como Asunto , Humanos , Propiedad/ética , Propiedad/legislación & jurisprudencia , Propiedad/normas
4.
Investig Genet ; 1(1): 3, 2010 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-21092337

RESUMEN

Through their current policy on data sharing, the National Institutes of Health (NIH) are inadvertently placing a serious and potentially insuperable burden upon non-US researchers who perform patient-based genomics studies in collaboration with US institutions. Because this policy could adversely affect future transnational scientific collaborations, we explore some of its likely consequences and suggest possible courses of remedial action wherever feasible.

5.
Eur J Hum Genet ; 18(5): 522-5, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-19953124

RESUMEN

The international transfer of human biomaterial and data has become a prerequisite for collaborative biomedical research to be successful. However, although a national legal framework for 'biobanking' has already been formulated in many countries, little is known about how an international exchange of data and samples might affect the legal position of national biobanks and their donors. The German Telematics Platform and the Competence Network 'Congenital Heart Defects' jointly instigated a project (BMB-EUCoop) to (i) identify and assess the legal risks ensuing for biobanks and their donors in the context of Europe-wide research collaborations, (ii) devise practical recommendations to minimize or avoid these risks, and (iii) provide generic informational text, contracts and agreements to facilitate their practical implementation. Four different countries were included in the study; namely, the UK, Netherlands, Austria and Switzerland. The results of the study indicate that the degree of similarity between legal systems in different countries varies according to the respective field of jurisdiction. Although personality and property rights have long been enshrined in virtually identical pieces of law, the applicable medical professional regulations were found to be somewhat heterogeneous. Furthermore, clear-cut differences were often found to be lacking between regulations that reflect either 'soft law' or the nationally binding 'hard law' that has emerged from it. In view of the potential ambiguities, the experts uniformly concluded that the rights and interests of national (in this case, German) biobanks and their donors would be best protected by explicitly addressing any uncertainties in formal contractual agreements.


Asunto(s)
Cooperación Internacional/legislación & jurisprudencia , Bancos de Tejidos/ética , Bancos de Tejidos/legislación & jurisprudencia , Alemania , Humanos , Propiedad/ética , Propiedad/legislación & jurisprudencia
6.
EMBO Rep ; 8(9): 839-45, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17721439

RESUMEN

The oxidative-stress-responsive kinase 1 (OSR1) and the STE20/SPS1-related proline/alanine-rich kinase (SPAK) are key enzymes in a signalling cascade regulating the activity of Na(+)/K(+)/2Cl(-) co-transporters (NKCCs) in response to osmotic stress. Both kinases have a conserved carboxy-terminal (CCT) domain, which recognizes a unique peptide (Arg-Phe-Xaa-Val) motif present in OSR1- and SPAK-activating kinases (with-no-lysine kinase 1 (WNK1) and WNK4) as well as its substrates (NKCC1 and NKCC2). Here, we describe the structural basis of this recognition event as shown by the crystal structure of the CCT domain of OSR1 in complex with a peptide containing this motif, derived from WNK4. The CCT domain forms a novel protein fold that interacts with the Arg-Phe-Xaa-Val motif through a surface-exposed groove. An intricate web of interactions is observed between the CCT domain and an Arg-Phe-Xaa-Val motif-containing peptide derived from WNK4. Mutational analysis shows that these interactions are required for the CCT domain to bind to WNK1 and NKCC1. The CCT domain structure also shows how phosphorylation of a Ser/Thr residue preceding the Arg-Phe-Xaa-Val motif results in a steric clash, promoting its dissociation from the CCT domain. These results provide the first molecular insight into the mechanism by which the SPAK and OSR1 kinases specifically recognize their upstream activators and downstream substrates.


Asunto(s)
Activadores de Enzimas/metabolismo , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Secuencia Conservada , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Péptidos/química , Péptidos/metabolismo , Fosforilación , Unión Proteica , Pliegue de Proteína , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Especificidad por Sustrato
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