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La piruvato quinasa M2 es un coactivador estimulado por PHD3 para el factor inducible por hipoxia 1 1
Weibo Luo1, Hongxia Hu, Ryan Chang
1Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell
|May 31, 2011
Resumen
La proteína piruvato quinasa M2 (PKM2) interactúa con el factor inducible a la hipoxia 1 (HIF-1) para mejorar la actividad génica de las células cancerosas y alterar el metabolismo de la glucosa. Esta interacción promueve el crecimiento tumoral y crea un bucle de retroalimentación para la función sostenida de las células cancerosas.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Investigación del cáncer Investigación del cáncer.
Sus antecedentes:
- La piruvatocinasa M2 (PKM2) es un producto alternadamente empalmado del gen PKM2, distinto de PKM1.
- PKM2 influye en el metabolismo de la glucosa de las células cancerosas y la tumorigénesis a través de mecanismos más allá de su actividad enzimática conocida.
Objetivo del estudio:
- Para investigar el papel de PKM2 en la regulación del metabolismo de la glucosa y la tumorigénesis.
- Aclarar los mecanismos moleculares por los cuales PKM2 afecta la actividad del factor inducible por hipoxia 1 (HIF-1).
Principales métodos:
- Investigó la activación de la transcripción del gen PKM2 por HIF-1.
- Analizó la interacción de PKM2 con HIF-1α y su efecto en la transactivación del gen diana HIF-1.
- Se examinó el papel de la prolyl hidroxilasa 3 (PHD3) en la función de PKM2 utilizando espectrometría de masas y ensayos de anticuerpos.
- Se evaluó el impacto de la eliminación de PHD3 en el metabolismo celular.
Principales resultados:
- PKM2, no PKM1, interactúa con HIF-1α, mejorando la unión de HIF-1 y el reclutamiento de p300 para promover la transactivación de los genes diana de HIF-1.
- La prolyl hidroxilasa 3 (PHD3) mejora la interacción de PKM2 con HIF-1α y su función de coactivador.
- PKM2 se hidroxila en la prolina-403/408, y el PHD3 knockdown perjudica la función del coactivador de PKM2, reduce la absorción de glucosa y la producción de lactato, y aumenta el consumo de oxígeno.
- PKM2 forma un bucle de retroalimentación positiva con HIF-1, reprogramando el metabolismo de la glucosa en las células cancerosas.
Conclusiones:
- PKM2 juega un papel crítico en la regulación del metabolismo de las células cancerosas y la promoción de la tumorigénesis a través de su interacción con HIF-1.
- La interacción PKM2-HIF-1 representa un nuevo mecanismo para la reprogramación metabólica en el cáncer.
- Dirigirse a la vía PKM2-HIF-1 puede ofrecer estrategias terapéuticas para el tratamiento del cáncer.
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