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dc.contributor.advisorSánchez de Gómez, Myriam
dc.creatorVallejo Pulido, Andrés Felipe
dc.date.accessioned2020-08-23T04:50:01Z
dc.date.available2020-08-23T04:50:01Z
dc.date.created2010-06-01
dc.identifier.urihttps://repositorio.unal.edu.co/handle/unal/78186
dc.descriptionLas células son dispositivos de procesamiento de información, que integran millones de señales extracelulares e intracelulares para producir una respuesta celular óptima dentro de un organismo. Muchas enfermedades, por ejemplo el cáncer, pueden ser entendidas como alteraciones patológicas en las redes de señalización. Por lo que el estudio de los mecanismos de procesamiento de señales constituye uno de los problemas más complejos y al mismo tiempo más significativos en las investigaciones biológicas. Los eventos de señalización incluyen intrincadas redes de señalización, que encierran “loops” de retroalimentación, señalización cruzada con otras redes y la integración del estado interno de la célula, todos estos, regulados espacial y temporalmente. El sistema de señalización de los IGFs es una compleja red regulatoria que tiene funciones en todo el organismo, a nivel celular y subcelular. El sistema IGF está relacionado con el desarrollo del organismo y mantenimiento de la función celular normal. Además, ha sido relacionado en diversas condiciones patológicas con un papel particularmente importante en cáncer. Las similaridades estructurales entre el receptor de IGF y el receptor de insulina, permiten la formación de receptores híbridos, en donde una cadena IGF-1R αβ está conectada a una cadena InsR-A o InsR-B. Cuando se coexpresan los receptores de IGF y de insulina en la misma célula, estos receptores híbridos pueden formarse aleatoriamente y representan el tipo de receptor más abundante. Sin embargo, se conoce muy poco sobre su importancia en la transducción de señales y de los efectos biológicos que pueden estar modulando; este trabajo aborda el problema del estudio de la señalización del sistema IGF desde una perspectiva integradora que refleja el entorno biológico en el que se encuentra; haciendo uso tanto de técnicas clásicas de análisis, como técnicas de vanguardia se buscó entender los mecanismos que subyacen en el procesamiento de señales que desencadena en un efecto biológico. Las células de trofoblasto hacen parte de la placenta y son las encargadas de invadir el endometrio materno durante el proceso de implantación del blastocisto, además, evaden los efectores de la respuesta inmune materna, siendo de vital importancia para el desarrollo fetoplacental. La invasión del trofoblasto a la matriz extracelular del útero es un ejemplo de invasión altamente controlada. Este proceso comparte muchas características con tumores metastásicos, sin embargo se encuentra regulado espacial y temporalmente. A partir de la línea de trofoblasto HTR8, se obtuvieron dos líneas celulares establemente silenciadas en los receptores IGF-1R e IGF-2R/M6P con las que se realizaron ensayos de proliferación, migración, invasión, expresión de Mmp-9 y cAMP, paralelamente se efectuó un estudio proteómico de las proteínas activadas por IGF-2 en los modelos normal y silenciados con miras a obtener una visión integral delos fenómenos biológicos inducidos en la célula luego de la estimulación con IGFs. Los resultaron mostraron que los ligandos IGF son mediadores importantes de los fenómenos malignos compartidos entre las células de trofoblasto y las células cancerosas, tales como proliferación, migración e invasión. Estos efectos son mediados por los receptores híbridos InsR/IGF-1R y en ellos participan decenas de proteínas que fueron identificadas por medio de espectrometría de masas. Se estudiaron proteínas activadas por IGF-2 y se construyeron, a partir de ellas, redes de interacción proteína-proteína relacionadas con los principales efectos mediados por este ligando en células trofoblásticas. Empleando electroforesis en dos dimensiones y el modelo celular silenciado para el receptor IGF-1R, se evaluó su papel al analizar los cambios inducidos por su depleción en los mapas activación de proteínas. Finalmente, se empleo la línea celular silenciada establemente en el receptor IGF-2/M6P para estudiar su papel en los efectos bilógicos mediados por los IGFs y en las redes de señalización. Se encontró que la presencia del receptor tipo 2 es clave en la migración, invasión y expresión de Mmp-9. Adicionalmente se obtuvo evidencia de que este receptor puede activar receptores acoplados a proteína G, probablemente con intermediación de la S1P. Este trabajo es el primer estudio que aborda el problema de la señalización del sistema IGF desde una visión que enmarca las proteínas dentro de complejas redes de señalización. Empleando técnicas de análisis de fosfoproteómica en conjunto con ensayos de actividad biológica, se presenta evidencia sólida de la estrecha relación entre los tres receptores del sistema IGF en la regulación de los efectos biológicos mediados por los ligandos IGF-1 e IGF-2. Además, muestra el papel central del receptor IGF-2/M6P en la transducción de señales del sistema IGF y como su ausencia genera cambios notorios en el fosfoproteoma que se ven reflejados en los fenómenos biológicos más importantes en cáncer, migración e invasión. Estos resultados amplían el conocimiento de la señalización mediada por los IGFs, destacan la importancia del receptor IGF-2/M6P como un mediador clave en los fenómenos de transducción de señales; representan el primer estudio a gran escala de las redes de señalización activadas por los IGFs y su relación con fenómenos biológicos importantes para el desarrollo del cáncer.
dc.description.abstractCells are information processing devices, which integrate millions of extracellular and intracellular signals to produce an optimal cellular response within of an organism. Many diseases, for example cancer, can be understood as pathological alterations in the signalling networks. Therefore, the study of the signal processing mechanisms constitutes one of the most complex and at the same time more significant in biological research questions. The signaling events include intricate signaling networks, which enclose "feedback loops, cross-signaling with other networks and the integration of the internal state of the cell, all of these, regulated spatially and temporally. The signalling system of the IGFs is a complex regulatory network that has functions throughout the body, at the cellular and sub-cellular levels. The IGF system isrelated to the development of the organism and maintenance of cell function normal. In addition, it has been linked in various pathological conditions to a role particularly important in cancer. The structural similarities between the receptor of IGF and the insulin receptor, allow the formation of hybrid receptors, where an IGF-1R αβ string is connected to an InsR-A or InsR-B string. When co-express IGF and insulin receptors in the same cell, these receptors hybrids can be formed randomly and represent the most abundant receptor form. However, very little is known about its importance in transduction of signals and the biological effects they may be modulating; this paper addresses the problem of studying the signalling of the IGF system from a that reflects the biological environment in which it is found; making use of both of classic analysis techniques, as well as avant-garde techniques, we sought to understand the mechanisms underlying the signal processing that triggers an effect biological. The trophoblast cells are part of the placenta and are responsible for invading the maternal endometrium during the blastocyst implantation process, furthermore, they evade the effectors of the maternal immune response, being of vital importance for the fetoplacental development. The invasion of the trophoblast into the extracellular matrix of the uterus is an example of a highly controlled invasion. This process shares many characteristics with metastatic tumors, however it is spatially regulated and temporarily. From the HTR8 trophoblast line, two lines were obtained Stably silenced cell phones in the IGF-1R and IGF-2R/M6P receptors with which proliferation, migration, invasion, MMP-9 expression and cAMP, a parallel proteomic study of the proteins activated by IGF-2 in normal and silenced models in order to obtain a comprehensive view of biological phenomena induced in the cell after IGF stimulation. The results showed that IGF ligands are important mediators of the malignant phenomena shared between trophoblast cells and cells cancers, such as proliferation, migration and invasion. These effects are mediated by the InsR/IGF-1R hybrid receptors and involve dozens of proteins that were identified by mass spectrometry. Proteins were studied activated by IGF-2 and built from them networks of interaction protein-protein related to the main effects mediated by this ligand in trophoblastic cells. Using two-dimensional electrophoresis and the cell model silenced for the IGF-1R receptor, its role was evaluated by analyzing the induced changes for their depletion in the protein activation maps. Finally, the silenced cell line was used stably in the IGF-2/M6P to study its role in IGF-mediated bilogical effects and in the signalling networks. The presence of the type 2 receptor was found to be key in the migration, invasion and expression of Mmp-9. Additionally, evidence was obtained that this receptor can activate G-protein-coupled receptors, probably with intermediation of the S1P. This work is the first study to address the problem of system signalling IGF from a vision that frames proteins within complex networks of signaling. Using phosphoprotein analysis techniques in conjunction with biological activity tests, there is strong evidence of the close relationship between the three receptors of the IGF system in the regulation of biological effects mediated by ligands IGF-1 and IGF-2. It also shows the central role of the IGF-2/M6P receptor in the signal transduction of the IGF system and how its absence generates noticeable changes in the phosphoprotein which are reflected in the most important biological agents in cancer, migration and invasion. These results extend the knowledge of the signaling mediated by the IGFs, highlight the importance of IGF-2/M6P receptor as a key mediator in the transduction phenomena of signals; they represent the first large-scale study of signalling networks activated by the IGFs and their relationship with biological phenomena important to the development of cancer.
dc.format.extent148
dc.format.mimetypeapplication/pdf
dc.language.isospa
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/2.5/co/
dc.subjectreceptores híbridos.
dc.subjectFosfoproteómica
dc.subjecttrofoblasto
dc.subject.ddc540 - Química y ciencias afines
dc.titleImportancia de los receptores híbridos receptor de insulina/receptor del factor de crecimiento similar a la insulina tipo I (InsR/IGF-1R) en las redes de señalización del sistema IGF
dc.typeOther
dc.rights.spaAcceso abierto
dc.contributor.institutionUniversidad Nacional de Colombia - Sede Bogotá
dc.subject.keywordtrophoblast
dc.subject.keywordhybrid receptors
dc.subject.keywordphosphoproteomics
dc.type.spaOtro
dc.type.hasversionAccepted Version
dc.coverage.programDepartamento de Química
dc.contributor.gruplacGrupo de Investigación en Hormonas
dc.coverage.modalityDoctorado
dc.rights.accessRightsOpen Access
dc.rights.ccAtribución-NoComercial-SinDerivadas 2.5 Colombia
dc.rights.ccAtribución-NoComercial-SinDerivadas 2.5 Colombia
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