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Stimulation of Notch Signaling in Mouse Osteoclast Precursors
Published on: February 28, 2017
Una nueva función supresora de tumores para la vía de Notch en la leucemia mieloide
Apostolos Klinakis1, Camille Lobry, Omar Abdel-Wahab
1Biomedical Research Foundation, Academy of Athens, Athens, Greece.
Nature
|May 13, 2011
Resumen
La señalización de la muesca normalmente regula la diferenciación celular. Este estudio encuentra que las mutaciones inactivantes en la señalización de Notch causan leucemia mielomonocítica crónica (LMC) al interrumpir la diferenciación de las células madre hematopoyéticas.
Área de la Ciencia:
- Hematología Hematología.
- Biología Molecular Biología Molecular
- Biología del cáncer Biología del cáncer.
Sus antecedentes:
- La señalización de muescas, regulada por el complejo γ-secretasa (γSE), es crucial para la diferenciación celular.
- Si bien la señalización de Notch tiene un doble papel en los tumores sólidos, es principalmente oncogénica en el sistema hematopoyético, por ejemplo, la leucemia linfoblástica aguda de células T.
- Su papel en la leucemia mielomonocítica crónica (LMMC) no ha sido claro.
Objetivo del estudio:
- Para investigar el papel de la señalización Notch en la leucemia mielomonocítica crónica (LMMC).
- Para identificar nuevas mutaciones que afectan a la vía de Notch en pacientes con LMCM.
- Para dilucidar las consecuencias funcionales de la inactivación de la vía de Notch en las células madre hematopoyéticas (HSC).
Principales métodos:
- Análisis de mutación somática en muestras de pacientes con LMCM.
- Inactivación de la señalización de Notch en las células madre hematopoyéticas de ratón (HSC).
- Análisis de las poblaciones de progenitores hematopoyéticos y la inducción de la enfermedad en ratones.
- Análisis del transcriptoma para identificar firmas de expresión génica reguladas.
Principales resultados:
- Se identificaron nuevas mutaciones somáticas inactivadoras en la vía de Notch en pacientes con LMCM.
- La inactivación de la señalización de Notch en HSCs de ratón condujo a la acumulación de progenitor de granulocitos / monocitos (GMP) y a una enfermedad similar a la CMML.
- Se descubrió que la señalización de la muesca regulaba una firma genética específica de los mielomonocitos.
- El objetivo de Notch, Hes1, suprime directamente la transcripción génica, mediando el papel regulador de Notch.
Conclusiones:
- La señalización de muescas juega un papel novedoso y supresor en la diferenciación temprana de HSC.
- La inactivación de la señalización de Notch contribuye a la patogénesis de la CMML.
- La vía de Notch exhibe funciones supresoras y promotoras de tumores dependientes del contexto dentro del mismo tejido.
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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...
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...
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...
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...
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
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...
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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02:54Canonical Wnt Signaling Pathway
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01:12Loss of Tumor Suppressor Gene Functions
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