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p27 activa alostéricamente la cinasa 4 dependiente de la ciclina y antagoniza la inhibición del palbociclib

Keelan Z Guiley^1,2, Jack W Stevenson², Kevin Lou²

¹Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA.

Science (New York, N.Y.)

|December 14, 2019

Resumen

La proteína p27 fosforilada activa la CDK4, promoviendo la proliferación celular. Este complejo activado es resistente al fármaco palbociclib, que se dirige a la CDK4 / 6 inactiva, revelando un nuevo mecanismo en el cáncer.

Área de la Ciencia:

Biología molecular
Regulación del ciclo celular
Terapia contra el cáncer

Sus antecedentes:

La proteína p27 inhibe típicamente las cinasas dependientes de la ciclina (CDK) para controlar la proliferación celular.
El mecanismo por el cual p27 se asocia con la CDK4 activa no está claro.
Comprender la regulación de la CDK es crucial para el tratamiento del cáncer.

Objetivo del estudio:

Para aclarar el mecanismo de activación de CDK4 por p27.
Investigar las consecuencias estructurales y funcionales de la fosforilación de p27.
Para determinar la sensibilidad del complejo p27-CDK4 a los inhibidores de la CDK4/6.

Principales métodos:

Ensayos de fosforilación de las proteínas con tirosina quinasa.
Análisis estructural de los complejos proteicos.
Ensayos bioquímicos para medir la actividad de la quinasa.
Pruebas de sensibilidad a fármacos con palbociclib.

Principales resultados:

La p27 fosforilada (phosp27) activa alostericamente la CDK4 en complejo con la ciclina D1 (CDK4-CycD1).
La unión con phosp27 altera el sitio activo de la CDK4, aumentando la fosforilación de sustratos como la proteína del retinoblastoma (Rb).
El complejo phosp27-CDK4-CycD1 es insensible al palbociclib, mientras que el fármaco ataca el monómero CDK4/6.

Conclusiones:

El p27 fosforilado forma un complejo activo de Rb quinasa (phosp27-CDK4-CycD1) con propiedades reguladoras únicas.
Este complejo representa una nueva forma de actividad CDK4/ 6 resistente a los fármacos.
Los hallazgos sugieren nuevas estrategias terapéuticas dirigidas a los complejos CDK4/ 6 resistentes en el cáncer.

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