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RESUMEN

The PSMD14 (POH1, also known as Rpn11/MPR1/S13/CepP1) protein within the 19S complex (19S cap; PA700) is responsible for substrate deubiquitination during proteasomal degradation. The role of PSMD14 in cell proliferation and senescence was explored using siRNA knockdown in carcinoma cell lines. Our results reveal that down-regulation of PSMD14 by siRNA transfection had a considerable impact on cell viability causing cell arrest in the G0-G1 phase, ultimately leading to senescence. The molecular events associated with decreased cell proliferation, cell cycle arrest and senescence include down-regulation of cyclin B1-CDK1-CDC25C, down-regulation of cyclin D1 and up-regulation of p21(/Cip) and p27(/Kip1). Most notably, phosphorylation of the retinoblastoma protein was markedly reduced in PSMD14 knockdown cells. A comparative study with PSMB5, a subunit of the 20S proteasome, revealed that PSMB5 and PSMD14 have different effects on cell cycle, senescence and associated molecular events. These data support the view that the 19S and 20S subunits of the proteasome have distinct biological functions and imply that targeting 19S and 20S would have distinct molecular consequences on tumor cells.

Asunto(s)

Ciclo Celular/genética , Senescencia Celular/genética , Complejo de la Endopetidasa Proteasomal/deficiencia , Transactivadores/deficiencia , Proteína Quinasa CDC2/genética , Proteína Quinasa CDC2/metabolismo , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/genética , Ciclina B1/genética , Ciclina B1/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/genética , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina/metabolismo , ADN/análisis , Células Epiteliales/citología , Células Epiteliales/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Fase G1/genética , Expresión Génica/genética , Células HeLa , Humanos , Fosforilación/genética , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , ARN Interferente Pequeño/genética , Fase de Descanso del Ciclo Celular/genética , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo , Sulfotransferasas/metabolismo , Transactivadores/genética , Transactivadores/metabolismo , Transfección , Proteínas Ubiquitinadas/metabolismo , Regulación hacia Arriba/genética , beta-Galactosidasa/metabolismo , Fosfatasas cdc25/genética , Fosfatasas cdc25/metabolismo

RESUMEN

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