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Regulación de la vía de señalización Miostatina/Smad3 mediada por IGF-1/PI3K/Akt durante la diferenciación de mioblastos
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Fecha
2013
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es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
Miostatina, también conocido como factor de crecimiento y diferenciación tipo 8 (GDF-
8) es una proteína perteneciente a la superfamilia de factores de transformación y crecimiento
TGF-B. Miostatina corresponde a un regulador negativo de la miogénesis que ejerce sus
funciones activando a factores de transcripción Smad que regulan negativamente la expresión de
genes involucrados en proliferación y diferenciación de mioblastos, dentro de los que destaca
myod. De manera antagónica, la proliferación y diferenciación de células musculares es
positivamente. regulada por la vía IGF-1/PBK/Akt. Ambas vías de señalización regulan
coordinadamente el desarrollo y crecimiento muscular, sin embargo, se desconocen los
mecanismos que participan en esta conversación cruzada.
Se ha determinado en diversos modelos celulares que la vía de señalización para IGF -1
puede inhibir etapas tempranas en la transducción de señales para TGF-B1. Estos estudios
demuestran que la proteína quinasa Akt, activada por IGF-1/PBK puede inhibir la fosforilación y
subsecuente translocación de Smad3. inducida por TGF-B1. Considerando que en la vía de
señalización para Miostatina participan intermediarios comunes a la vía de señalización para
TGF-B, proponemos como hipótesis de trabajo que "la vía de señalización IGF-l/PI3K/A"7
inhibe la activación de Smad3 inducida por Miostatina durante la diferenciación de
mioblastos". Para poner a prueba esta hipótesis, mioblastos en etapa de diferenciación fueron
estimulados con Miostatina recombinante, en presencia o ausencia de IGF-1, así como también
inhibidores específicos para las vías PBK/Akt y Smads. Análisis mediante las técnicas de vector
reportero, Western Blot y RT-PCR semicuantitativo demostraron que IGF-1 inhibe la vía de
señalización para Miostatina, así como también la regulación negativa de Miostatina en la
expresión de myod. Los resultados obtenidos demuestran que la vía de señalización IGF-
1/PI3K/Akt actúa río abajo de la activación de Smad3 inhibiendo la actividad transcripcional de
Smad suprimiendo el efecto inhibitorio de Miostatina en la expresión de genes involucrados en la
diferenciación del músculo esquelético como myod. Esperamos que esta información obtenida
durante el desarrollo de esta tesis nos ayude a profundizar los conocimientos respecto a las vías
de señalización involucradas en la miogénesis con potenciales aplicaciones en Biomedicina.
Myostatin, also known as growth differentiation factor-8 (GDF-8) is a protein belonging to the transforming gro"1h factor-B (TGF-B) superfamily. Myostatin corresponds to a negative regulator of myogenesis that exerts its functions by activating Smad transcription factors that negatively regulate the expression of genes involved in proliferation and differentiation of myoblasts such as myod. In an antagonistic manner, the proliferation and differentiation of muscle cells is regulated positively by the IGF-1/PBK/Akt pathway. Both signaling pathways coordinately regulate muscle growth and development, however, there are no reports about mechanisms involved in this cross-talk. It has been established in several cellular models that the IGF-1 signaling pathway may inh.i.bit early stages of TGF-Bl signal transduction. These studies demonstrate that Akt protein kinase activated by IGF-1/PBK can inhibit the phosphorylation of Smad3 and its subsequent translocation induced by TGF-Bl. Considering that in Myostatin and TGF-B signaling patlrn·ays participate common intermediaries. we propose as our ,Yorking hypothesis that "IGF-l/Pl3K/Akt signaling pathway inhibits Smad3 activation induced by Myostatin during myoblast dif/erentiation". To test this hypothesis. myoblasts in differentiation stage were stimulated with recombinant Myostatin in the presence or absence of IGF-1, and with specific inhibitors for PI3K/Akt and Smads signaling pathways. Analysis by lucifersase reporter vector, Western Blot and semi-quantitative RT-PCR techniques showed that IGF-1 inhibits Myostatin signaling pathway as well as the Myostatin-induced inhibition of myod expression. The results obtained demonstrate that the IGF-1/PI3K/Akt signaling pathway acts downstream Smad3 activation inhibiting the transcriptional activity of Smad suppressing the inhibitory effect of Myostatin in the expression of genes involved in skeletal muscle differentiation as myod. We hope our findings during this thesis will help to obtain more knowledge about signaling pathways involved in myogenesis with potential applications in Biomedicine.
Myostatin, also known as growth differentiation factor-8 (GDF-8) is a protein belonging to the transforming gro"1h factor-B (TGF-B) superfamily. Myostatin corresponds to a negative regulator of myogenesis that exerts its functions by activating Smad transcription factors that negatively regulate the expression of genes involved in proliferation and differentiation of myoblasts such as myod. In an antagonistic manner, the proliferation and differentiation of muscle cells is regulated positively by the IGF-1/PBK/Akt pathway. Both signaling pathways coordinately regulate muscle growth and development, however, there are no reports about mechanisms involved in this cross-talk. It has been established in several cellular models that the IGF-1 signaling pathway may inh.i.bit early stages of TGF-Bl signal transduction. These studies demonstrate that Akt protein kinase activated by IGF-1/PBK can inhibit the phosphorylation of Smad3 and its subsequent translocation induced by TGF-Bl. Considering that in Myostatin and TGF-B signaling patlrn·ays participate common intermediaries. we propose as our ,Yorking hypothesis that "IGF-l/Pl3K/Akt signaling pathway inhibits Smad3 activation induced by Myostatin during myoblast dif/erentiation". To test this hypothesis. myoblasts in differentiation stage were stimulated with recombinant Myostatin in the presence or absence of IGF-1, and with specific inhibitors for PI3K/Akt and Smads signaling pathways. Analysis by lucifersase reporter vector, Western Blot and semi-quantitative RT-PCR techniques showed that IGF-1 inhibits Myostatin signaling pathway as well as the Myostatin-induced inhibition of myod expression. The results obtained demonstrate that the IGF-1/PI3K/Akt signaling pathway acts downstream Smad3 activation inhibiting the transcriptional activity of Smad suppressing the inhibitory effect of Myostatin in the expression of genes involved in skeletal muscle differentiation as myod. We hope our findings during this thesis will help to obtain more knowledge about signaling pathways involved in myogenesis with potential applications in Biomedicine.
Notas
Tesis (Ingeniería en Biotecnología)
Palabras clave
Proteínas (Quinasa), Desarrollo y crecimiento muscular, Biomedicina, Chile