RESUMEN
The Aurora B abscission checkpoint delays cytokinesis until resolution of DNA trapped in the cleavage furrow. This process involves PKCε phosphorylation of Aurora B S227. Assessing if this PKCε-Aurora B module provides a more widely exploited genome-protective control for the cell cycle, we show Aurora B phosphorylation at S227 by PKCε also occurs during mitosis. Expression of Aurora B S227A phenocopies inhibition of PKCε in by-passing the delay and resolution at anaphase entry that is associated with non-disjunction and catenation of sister chromatids. Implementation of this anaphase delay is reflected in PKCε activation following cell cycle dependent cleavage by caspase 7; knock-down of caspase 7 phenocopies PKCε loss, in a manner rescued by ectopically expressing/generating a free PKCε catalytic domain. Molecular dynamics indicates that Aurora B S227 phosphorylation induces conformational changes and this manifests in a profound switch in specificity towards S29 TopoIIα phosphorylation, a response necessary for catenation resolution during mitosis.
Asunto(s)
Anafase/fisiología , Aurora Quinasa B/metabolismo , Metafase/fisiología , Mitosis/fisiología , Anafase/genética , Aurora Quinasa B/química , Aurora Quinasa B/genética , Caspasa 7/metabolismo , Proteínas de Ciclo Celular/metabolismo , Cromátides/metabolismo , Cromatina , Cromosomas/metabolismo , Células HEK293 , Humanos , Metafase/genética , Mitosis/genética , Simulación de Dinámica Molecular , Fosforilación , Proteína Quinasa C-epsilon/metabolismo , Proteínas Recombinantes , Transducción de Señal/fisiologíaRESUMEN
Associated with their roles as targets for tumour promoters, there has been a long-standing interest in how members of the protein kinase C (PKC) family act to modulate cell growth and division. This has generated a great deal of observational data, but has for the most part not afforded clear mechanistic insights into the control mechanisms at play. Here, we review the roles of PKCε in protecting transformed cells from non-disjunction. In this particular cell cycle context, there is a growing understanding of the pathways involved, affording biomarker and interventional insights and opportunities.
Asunto(s)
Genómica , Neoplasias/genética , Proteína Quinasa C-epsilon/metabolismo , Proliferación Celular , Humanos , Neoplasias/enzimología , Neoplasias/patologíaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.