p27 activa alostéricamente la cinasa 4 dependiente de la ciclina y antagoniza la inhibición del palbociclib
Contact us if these videos are not relevant.
Contact us if these videos are not relevant.
Ver abstracta en PubMed
Resumen
Este resumen es generado por máquina.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.
Contact us Si estos videos no son relevantes.
Contact us Si estos videos no son relevantes.
Videos de Conceptos Relacionados
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
Three of the best-understood negative regulators are p53, p21, and retinoblastoma protein (Rb). The regulatory roles of each of these proteins were discovered after faulty copies were found in cells with uncontrolled replication (i.e.,...
Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.
Internal regulatory checkpoints ensure that a cell’s size, energy reserves, and DNA quality and completeness are sufficient to advance through the cell cycle. At these checkpoints, positive and negative regulators promote or inhibit a cell’s continuation through the cell cycle.
Positive regulators include two protein groups that allow cells to...
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...