RESUMEN
The anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase is known to target the degradation of cyclin B1, which is crucial for mitotic progression in animal cells. In this study, we show that the ubiquitin ligase CRL2ZYG-11 redundantly targets the degradation of cyclin B1 in Caenorhabditis elegans and human cells. In C. elegans, both CRL2ZYG-11 and APC/C are required for proper progression through meiotic divisions. In human cells, inactivation of CRL2ZYG11A/B has minimal effects on mitotic progression when APC/C is active. However, when APC/C is inactivated or cyclin B1 is overexpressed, CRL2ZYG11A/B-mediated degradation of cyclin B1 is required for normal progression through metaphase. Mitotic cells arrested by the spindle assembly checkpoint, which inactivates APC/C, often exit mitosis in a process termed "mitotic slippage," which generates tetraploid cells and limits the effectiveness of antimitotic chemotherapy drugs. We show that ZYG11A/B subunit knockdown, or broad cullin-RING ubiquitin ligase inactivation with the small molecule MLN4924, inhibits mitotic slippage in human cells, suggesting the potential for antimitotic combination therapy.
Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/citología , Caenorhabditis elegans/metabolismo , Proteínas de Ciclo Celular/metabolismo , Ciclina B1/metabolismo , Mitosis , Proteolisis , Ciclosoma-Complejo Promotor de la Anafase/metabolismo , Animales , Proteína Quinasa CDC2/metabolismo , Caenorhabditis elegans/efectos de los fármacos , Línea Celular Tumoral , Células HEK293 , Humanos , Mitosis/efectos de los fármacos , Nocodazol/farmacología , Unión Proteica/efectos de los fármacos , Proteolisis/efectos de los fármacos , Especificidad por Sustrato/efectos de los fármacos , Imagen de Lapso de TiempoRESUMEN
The oocyte-to-embryo transition requires drastic reorganizations within a short timeframe. Recent studies show that, in the nematode Caenorhabditis elegans, phosphotyrosine-binding pseudo-phosphatases are key regulators of this critical developmental transition.