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La inhibición de la notch/gamma-secretasa convierte a las células proliferativas en las criptas intestinales y los
Johan H van Es1, Marielle E van Gijn, Orbicia Riccio
1Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
Nature
|June 17, 2005
Resumen
En el intestino delgado, el bloqueo de la vía de Notch convierte rápidamente las células proliferativas en células de copa. Este hallazgo sugiere que los inhibidores de la gamma secretasa podrían tratar el cáncer colorrectal.
Área de la Ciencia:
- Biología celular Biología celular.
- Gastroenterología y Gastroenterología.
- Investigación del cáncer investigación del cáncer.
Sus antecedentes:
- El epitelio intestinal se renueva a sí mismo a través de células madre / progenitoras en criptas y células diferenciadas en vellosidades.
- La vía de señalización Wnt es crucial para la determinación del destino celular a lo largo del eje cripta-vilo.
- El papel de la vía Notch en el mantenimiento de las células madre intestinales está siendo investigado.
Objetivo del estudio:
- Investigar el papel de la vía de Notch en el mantenimiento de las células madre y progenitoras intestinales.
- Explorar el potencial terapéutico de dirigirse a la vía de Notch en la neoplasia colorrectal.
Principales métodos:
- Eliminación condicional del factor de transcripción de la vía de Notch CSL/RBP-J en ratones.
- Inhibición farmacológica de la cascada de Notch utilizando un inhibidor de la gamma secretasa.
- Análisis de la diferenciación y proliferación de células de copa en criptas intestinales y adenomas de ratón.
Principales resultados:
- La eliminación condicional de CSL / RBP-J indujo una conversión rápida y masiva de las células criptográficas proliferativas en células de copa.
- La inhibición de la gamma-secretasa imitaba este efecto, induciendo la diferenciación de las células del cáliz.
- Las vías de Notch y Wnt actúan de manera concertada para mantener células no diferenciadas y proliferativas en criptas y adenomas.
- Los inhibidores de la gamma-secretasa indujeron la diferenciación de células de copa en adenomas de ratón mutante Apc.
Conclusiones:
- La activación concertada de la señalización Notch y Wnt es esencial para mantener las células proliferativas en las criptas intestinales y los adenomas.
- Los inhibidores de la gamma secretasa, desarrollados para la enfermedad de Alzheimer, muestran potencial como estrategia terapéutica para las enfermedades neoplásicas colorrectales.
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The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
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03:14Notch Signaling Pathway
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
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Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
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