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Las proteínas HnRNP controladas por c-Myc desregulan la piruvato quinasa en el empalme del ARNm en el cáncer
Charles J David1, Mo Chen, Marcela Assanah
1Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Nature
|December 17, 2009
Resumen
Las células cancerosas utilizan la glicólisis aeróbica para el crecimiento mediante la expresión de la isoforma embrionaria de piruvato quinasa (PKM2). Este estudio identifica hnRNPs y c-Myc como reguladores clave del empalme de PKM2, crucial para la proliferación tumoral.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Biología del cáncer Biología del cáncer.
- Metabolismo celular El metabolismo celular es el metabolismo celular.
Sus antecedentes:
- Las células quiescentes utilizan la fosforilación oxidativa, mientras que las células tumorales muestran glicólisis aeróbica, convirtiendo la glucosa en lactato incluso con oxígeno.
- La glucólisis aeróbica es vital para el crecimiento de las células tumorales y está regulada por la expresión de la isoforma de piruvato quinasa (PK).
- La isoforma embrionaria de PKM2 promueve la glucólisis aeróbica y se reexpresa en el cáncer, en contraste con la isoforma adulta de PKM1 que favorece la fosforilación oxidativa.
Objetivo del estudio:
- Aclarar el mecanismo regulador que controla el empalme alternativo del pre-ARNm de PKM, lo que lleva a la inclusión de PKM2 en el cáncer.
- Investigar el papel de las ribonucleoproteínas nucleares heterogéneas (hnRNP) y c-Myc en la expresión de PKM2 y su relación con la proliferación tumoral.
Principales métodos:
- Análisis de eventos alternativos de empalme en el pre-ARNm.PKM.
- Identificación de las proteínas hnRNP que se unen a las secuencias reguladoras.
- Investigación del papel de c-Myc en la regulación de la expresión de hnRNP.
- Análisis de correlación de la expresión de proteínas en gliomas humanos.
Principales resultados:
- Se encontró que tres hnRNP (PTB, hnRNPA1, hnRNPA2) se unen de manera represiva a las secuencias que flanquean el exón 9, promoviendo la inclusión del exón 10 (PKM2).
- El factor de transcripción oncogénico c-Myc regula al alza PTB, hnRNPA1 y hnRNPA2, aumentando así la relación PKM2/PKM1.
- Los gliomas humanos muestran una sobreexpresión de c-Myc, PTB, hnRNPA1 y hnRNPA2, que se correlaciona con la expresión de PKM2.
Conclusiones:
- Una nueva vía que involucra hnRNPs y c-Myc regula el empalme alternativo de PKM, favoreciendo la expresión de PKM2 en el cáncer.
- Esta vía es esencial para mantener la alta proporción de PKM2 / PKM1 requerida para la proliferación de células tumorales.
- Los hallazgos proporcionan información sobre la reprogramación metabólica crítica para el crecimiento tumoral y sugieren posibles objetivos terapéuticos.
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