Publication: Identificación de compuestos activadores, proteínas moduladoras y sustratos de la MAPK Slt2 de la ruta de integridad celular de Saccharomyces cerevisiae
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2017-06-30
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Universidad Complutense de Madrid
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Abstract
Una propiedad fundamental de toda célula es su capacidad de detectar cambios en las condiciones ambientales, y actuar adecuadamente frente a ellos para así adaptarse. En este proceso son determinantes las rutas de transducción de señales mediadas por proteín quinasas activadas por mitógenos (MAPKs). En la parte final de estas rutas, donde opera el módulo de MAPKs formado por tres proteín quinasas, la señal se transmite de una a otra por fosforilaciones secuenciales, permitiendo así la amplificación de las señales iniciadas en la superficie celular (Cargnello et al., 2012). Una vez activada, la MAPK fosforila a distintos elementos entre los cuales se encuentran factores de tanscripción (Chen y Thorner, 2007). Así se genera una respuesta adecuada que generalmente implica una modificación de la expresión génica, junto con otros cambios en la fisiología celular. Las MAPKs regulan una gran variedad de procesos biológicos esenciales como el metabolismo, la morfología celular o la progresión del ciclo celular. Debido a que muchos de los componentes de estas rutas y mecanismos por los cuales operan están conservados, la investigación realizada en la levadura Saccharomyces cerevisiae ha proporcionado gran parte del conocimiento que se tiene actualmente de las rutas de MAPKs de organismos eucarióticos. En S. cerevisiae, una de estas rutas es la de integridad celular (CWI, Cell Wall Integrity), en la que la MAPK Slt2 es un componente fundamental activado por las MAPKKs Mkk1 y Mkk2. Esta ruta se activa por la alteración de la pared celular y conduce a la fosforilación del factor de transcripción Rlm1, responsable de la mayor parte de la respuesta transcripcional que se genera como mecanismo compensatorio para salvaguardar la integridad de esta estructura externa esencial (Levin, 2011). Esta ruta es de gran importancia, ya que la pared celular de los hongos es una buena diana farmacológica, al no estar presente en células humanas...
A fundamental property of every cell is its ability to detect changes in environmental conditions and take appropriate action against them in order to adapt. In this process, transduction pathways mediated by mitogen activated protein kinases (MAPKs) are decisive. At the end of these routes, the signal is transmitted from one element to another by sequential phosphorylations, allowing amplification of signals initiated at the cell surface (Cargnello et al., 2012). Once activated, the MAPK phosphorylates various elements including transcription factors (Chen and Thorner, 2007). Thus an adequate response is generated that involves gene expression modification and other changes in cell physiology. MAPKs regulate a variety of essential biological processes such as metabolism, cell morphology or cell cycle progression. Because many of the components of these pathways and mechanisms by which they operate are conserved, research in the yeast Saccharomyces cerevisiae has provided much of the knowledge we have today about MAPKs pathways in eukaryotic organisms. In S. cerevisiae, one of these routes is the cell wall integrity pathway (CWI) in which the MAPK Slt2 is activated by the MAPKKs Mkk1 and Mkk2. This pathway is activated by changes in the cell wall and leads to phosphorylation of the transcription factor Rlm1, which is responsible for most of the transcriptional response generated like a compensatory mechanism to safeguard the integrity of this essential structure (Levin, 2011). This route is of great importance, because the cell wall of fungi is a good drug target as it is not present in human cells...
A fundamental property of every cell is its ability to detect changes in environmental conditions and take appropriate action against them in order to adapt. In this process, transduction pathways mediated by mitogen activated protein kinases (MAPKs) are decisive. At the end of these routes, the signal is transmitted from one element to another by sequential phosphorylations, allowing amplification of signals initiated at the cell surface (Cargnello et al., 2012). Once activated, the MAPK phosphorylates various elements including transcription factors (Chen and Thorner, 2007). Thus an adequate response is generated that involves gene expression modification and other changes in cell physiology. MAPKs regulate a variety of essential biological processes such as metabolism, cell morphology or cell cycle progression. Because many of the components of these pathways and mechanisms by which they operate are conserved, research in the yeast Saccharomyces cerevisiae has provided much of the knowledge we have today about MAPKs pathways in eukaryotic organisms. In S. cerevisiae, one of these routes is the cell wall integrity pathway (CWI) in which the MAPK Slt2 is activated by the MAPKKs Mkk1 and Mkk2. This pathway is activated by changes in the cell wall and leads to phosphorylation of the transcription factor Rlm1, which is responsible for most of the transcriptional response generated like a compensatory mechanism to safeguard the integrity of this essential structure (Levin, 2011). This route is of great importance, because the cell wall of fungi is a good drug target as it is not present in human cells...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Microbiología II, leída el 10/06/2016