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La pérdida de la actividad CDK4/6 en la fase S/G2 conduce a la reversión del ciclo celular
James A Cornwell1, Adrijana Crncec1, Marwa M Afifi1
1Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Nature
|July 5, 2023
Resumen
El punto de restricción del ciclo celular es reversible. Las células de mamíferos salen del ciclo celular sin mitógenos a menos que se dividan, revelando una nueva comprensión del control de la proliferación celular.
Área de la Ciencia:
- Biología celular
- Biología molecular
- La bioquímica
Sus antecedentes:
- El punto de restricción en la progresión del ciclo celular de los mamíferos se considera tradicionalmente como un compromiso irreversible con la proliferación.
- Este compromiso está vinculado a un circuito de retroalimentación positiva que involucra a la ciclina A2 / quinasa dependiente de la ciclina 2 (CDK2) y la proteína del retinoblastoma, activada por la señalización del mitógeno.
Objetivo del estudio:
- Desafiar el modelo establecido del punto de restricción.
- Investigar la reversibilidad de la decisión de proliferación en las células de mamíferos.
- Elucidar los mecanismos moleculares que rigen la salida del ciclo celular en ausencia de mitógenos.
Principales métodos:
- El estudio probablemente involucró experimentos de cultivo celular con disponibilidad variable de mitógenos.
- Análisis de los niveles de proteínas y las actividades de la quinasa, centrándose específicamente en la ciclina A2, CDK2 y CDK4/6.
- Experimentos en el curso del tiempo para observar la progresión del ciclo celular y el destino después de la retirada de mitógenos.
Principales resultados:
- La decisión de proliferar en el punto de restricción es totalmente reversible.
- Las células que carecen de mitógenos saldrán del ciclo celular a menos que alcancen la mitosis y se dividan.
- La actividad de la ciclina A2/CDK2 depende de la actividad de la CDK4/6 durante todo el ciclo celular, no sólo en G1.
- La mitosis ocurre sin mitógenos solo si la vida media de la proteína ciclina A2 mantiene la actividad de CDK2 a través de G2/M.
Conclusiones:
- La señalización del mitógeno y la actividad de la CDK4/ 6 son cruciales para mantener la actividad de la CDK2 y la fosforilación de la proteína del retinoblastoma durante toda la interfase.
- La pérdida de la señalización mitogénica puede inducir rápidamente la salida del ciclo celular, incluso con breves retrasos en la progresión del ciclo celular.
- Los hallazgos revelan la base molecular del punto de restricción y destacan un papel crítico para CDK4/ 6 en las fases S y G2.
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