Publication: Mecanismos moleculares de regulación de la vía mTORC1/p70S6K, autofagia y mitofagia: papel de TSC2
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2017-07-13
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Universidad Complutense de Madrid
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Abstract
La diabetes mellitus tipo 2 (DMT2) está caracterizada por una primera fase en la cual el evento principal es la alteración en la acción de la insulina, denominado resistencia a la acción de la insulina, con niveles normales de glucemia. Durante esta fase, las células βpancreáticasexperimentan un proceso de hiperplasia y de hipertrofia, junto con un aumento en la secreción de insulina para compensar la hiperglucemia (Prentky, M et al. 2006). La duración de dicha fase depende de unos pacientes a otros y, en una etapa final, las células β pancreáticas experimentan un fallo, con la aparición de una hipoinsulinemia manifiesta. Durante la progresión a la DMT2, se ha observado una hiperactivación de la vía del complejo 1 diana de rapamicina en mamíferos (mTORC1), lo cual es beneficioso en la primera fase debido a que activa la proliferación celular de las células β. Sin embargo, la hiperactivación de mTORC1 de manera crónica contribuye al aumento del estrés de retículo endoplasmático (RE), y al fracaso de la célula β. Recientemente, nuestro grupo de investigación está centrado en el estudio de la vía de señalización que converge en mTORC1. El complejo de esclerosis tuberosa está formado por las proteínas hamartina (TSC1) y tuberina (TSC2) y funciona como un nexo de integración de señales energéticas y factores de crecimiento. La proteína TSC2 presenta en su estructura un dominio GAP, el cual activa la actividad GTPásica intrínseca de Rheb, promoviendo su inhibición, y como consecuencia, inhibe a mTORC1. El complejo mTORC1 regula numerosos procesos biológicos, entre los que destacan la proliferación, la síntesis de proteínas y la inhibición de la autofagia. La autofagia es un mecanismo fisiológico de control de calidad citoplasmático, cuya función principal es la eliminación de proteínas u orgánulos dañados, atenuando el efecto del estrés de RE. La importancia de la autofagia en el mantenimiento de la homeostasis de las células β pancreáticas se ha puesto de manifiesto en los últimos años (Jung H.S.et al., 2008; Ebato, C.et al. 2008)...
Type 2 Diabetes Mellitus (T2DM) is characterised by a first phase in which the principal event is the defect in the insulin’s action, called insulin resistance, accompanied with normoglycemia. During this phase, pancreatic β cells increased its cell number (hyperplasia) and its cell size (hypertrophy), along with an increase in insulin secretion in order to compensate hyperglycemia (Prentky, M et al. 2006). The duration of this phase is different in each patient, and finally, β cells begin to fail, and hypoinsulinemia appears. During T2DM progression, it was observed a hyperactivation of the complex 1 of the mammalian target of rapamycin (mTORC1), which is beneficial in the first phase due to an increase in β cell proliferation. However, the chronic mTORC1 hyperactivation drives to an increase in endoplasmic reticulum (ER) stress, and βcell failure. Recently, our group is focused on the study of mTORC1 pathway. Tuberous sclerosis complex, formed by two proteins called hamartin (TSC1) and tuberin (TSC2), acts an integrator of energetic signals and growth factors. TSC2 protein presents a GAP domain, which activates Rheb intrisic GTPase activity, promoting its inhibition, and as a consequence, mTORC1 inhibition. The mTORC1 signaling regulates numerous biological processes, such as proliferation, protein synthesis and autophagy inhibition. Autophagy is a physiological mechanism of cytoplasmic quality control, which its main function is the elimination of damaged proteins and organelles, diminishing ER-stress. Autophagy plays an important role in the maintaining β cells homeostasis (Jung H.S. et al., 2008; Ebato, C. et al. 2008)...
Type 2 Diabetes Mellitus (T2DM) is characterised by a first phase in which the principal event is the defect in the insulin’s action, called insulin resistance, accompanied with normoglycemia. During this phase, pancreatic β cells increased its cell number (hyperplasia) and its cell size (hypertrophy), along with an increase in insulin secretion in order to compensate hyperglycemia (Prentky, M et al. 2006). The duration of this phase is different in each patient, and finally, β cells begin to fail, and hypoinsulinemia appears. During T2DM progression, it was observed a hyperactivation of the complex 1 of the mammalian target of rapamycin (mTORC1), which is beneficial in the first phase due to an increase in β cell proliferation. However, the chronic mTORC1 hyperactivation drives to an increase in endoplasmic reticulum (ER) stress, and βcell failure. Recently, our group is focused on the study of mTORC1 pathway. Tuberous sclerosis complex, formed by two proteins called hamartin (TSC1) and tuberin (TSC2), acts an integrator of energetic signals and growth factors. TSC2 protein presents a GAP domain, which activates Rheb intrisic GTPase activity, promoting its inhibition, and as a consequence, mTORC1 inhibition. The mTORC1 signaling regulates numerous biological processes, such as proliferation, protein synthesis and autophagy inhibition. Autophagy is a physiological mechanism of cytoplasmic quality control, which its main function is the elimination of damaged proteins and organelles, diminishing ER-stress. Autophagy plays an important role in the maintaining β cells homeostasis (Jung H.S. et al., 2008; Ebato, C. et al. 2008)...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular II, leída el 23/11/2016