Publication: ICAP-1 regula la adhesión celular mediada por VLA-4 y el desarrollo del sistema inmunitario. Caracterización de relaciones entre VLA-4 y resistencia a bortezomib en mieloma múltiple
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2019-11-29
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Universidad Complutense de Madrid
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Abstract
La integrina α4β1 desempeña importantes funciones durante la migración linfocitaria hacia sitios de inflamación y en diferentes etapas de la hematopoyesis. La actividad de esta integrina está regulada por proteínas intracelulares que se asocian al dominio citoplasmático de la subunidad β1. Mientras que se han realizado numerosos estudios acerca de los reguladores positivos de las integrinas tales como talina y kindlin, aquellas proteínas que regulan negativamente su activación han sido menos caracterizadas, como es el caso de ICAP-1. Puesto que α4β1 se expresa en linfocitos, hemos estudiado el efecto de la falta de ICAP-1 en la adhesión dependiente de α4β1 en estas células, así como en la diferenciación de células del sistema inmunitario en el timo, bazo y médula ósea (MO). Otra de las funciones conocidas de α4β1 es su participación en la interacción entre células de mieloma múltiple (MM) y la microvasculatura de la MO y células del estroma medular. Esta interacción favorece la proliferación, supervivencia y resistencia a quimioterapia de las células de MM, promoviendo la colonización de la MO y la progresión de la enfermedad. Debido a que ICAP-1 se postula como regulador negativo de la activación de integrinas β1, es importante estudiar su papel en la adhesión de células de MM dependiente de α4β1. El Bortezomib (BTZ) es un inhibidor del proteasoma ampliamente utilizado en el tratamiento frente al MM. Desafortunadamente, muchos pacientes acaban desarrollando resistencia al BTZ, por lo que es crucial investigar los mecanismos que utilizan las células de MM para sobrevivir al tratamiento con este agente, incluyendo una posible relación entre el BTZ y la integrina α4β1...
The integrin α4β1 plays important roles during lymphocyte migration to sites of inflammation and at distinct steps in hematopoiesis. The activity of this integrin is regulated by intracellular proteins which associate with the β1 subunit cytoplasmic domain. While much is known on positive regulators such as talin and kindlin, less is known about those which negatively regulate integrin activation, such as ICAP-1. As α4β1 is expressed on lymphocytes, we have studied the effects of the lack of ICAP-1 on α4β1-dependent lymphocyte adhesion and on immune cell differentiation in thymus, spleen and bone marrow (BM). α4β1 also mediates the interaction between multiple myeloma (MM) cells and the BM microvasculature, as well as with BM stromal cells. This interaction favours MM cell proliferation, survival and resistance to chemotherapy, leading to BM colonization and disease progression. Given the potential role of ICAP-1 as negative regulator of β1 integrin activation, it is important to study its role on α4β1-dependent MM cell adhesion. Bortezomib (BTZ) is a proteasome inhibitor widely used in the treatment against MM. Unfortunately, many patients develop resistance to BTZ, and therefore is crucial to investigate the mechanisms that the MM cells use to bypass this inhibitor, including thepossible relationships between BTZ and α4β1...
The integrin α4β1 plays important roles during lymphocyte migration to sites of inflammation and at distinct steps in hematopoiesis. The activity of this integrin is regulated by intracellular proteins which associate with the β1 subunit cytoplasmic domain. While much is known on positive regulators such as talin and kindlin, less is known about those which negatively regulate integrin activation, such as ICAP-1. As α4β1 is expressed on lymphocytes, we have studied the effects of the lack of ICAP-1 on α4β1-dependent lymphocyte adhesion and on immune cell differentiation in thymus, spleen and bone marrow (BM). α4β1 also mediates the interaction between multiple myeloma (MM) cells and the BM microvasculature, as well as with BM stromal cells. This interaction favours MM cell proliferation, survival and resistance to chemotherapy, leading to BM colonization and disease progression. Given the potential role of ICAP-1 as negative regulator of β1 integrin activation, it is important to study its role on α4β1-dependent MM cell adhesion. Bortezomib (BTZ) is a proteasome inhibitor widely used in the treatment against MM. Unfortunately, many patients develop resistance to BTZ, and therefore is crucial to investigate the mechanisms that the MM cells use to bypass this inhibitor, including thepossible relationships between BTZ and α4β1...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, Departamento de Bioquímica y Biología Molecular, leída el 18/11/2019