RESUMEN

PolyADP-ribose polymerases (PARPs) catalyze a posttranslational modification of nuclear proteins by polyADP-ribosylation. The catalytic activity of the abundant nuclear protein PARP-1 is stimulated by DNA strand breaks, and PARP-1 activation is required for initiation of DNA repair. Here we show that PARP-1 also acts within extracellular signal-regulated kinase (ERK) signaling cascade that mediates growth and differentiation. The findings reveal an alternative mode of PARP-1 activation, which does not involve binding to DNA or DNA damage. In a cell-free system, recombinant PARP-1 was intensively activated and thereby polyADP-ribosylated by a direct interaction with phosphorylated ERK2, and the activated PARP-1 dramatically increased ERK2-catalyzed phosphorylation of the transcription factor Elk1. In cortical neurons treated with nerve growth factors and in stimulated cardiomyocytes, PARP-1 activation enhanced ERK-induced Elk1-phosphorylation, core histone acetylation, and transcription of the Elk1-target gene c-fos. These findings constitute evidence for PARP-1 activity within the ERK signal-transduction pathway.

Asunto(s)

Histonas/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteína Elk-1 con Dominio ets/metabolismo , Acetilación , Animales , Secuencia de Bases , Encéfalo/metabolismo , Núcleo Celular/metabolismo , Sistema Libre de Células , Células Cultivadas , ADN/metabolismo , Activación Enzimática , Expresión Génica , Genes fos , Técnicas In Vitro , Sistema de Señalización de MAP Quinasas , Proteína Quinasa 1 Activada por Mitógenos/genética , Modelos Biológicos , Fosforilación , Poli(ADP-Ribosa) Polimerasa-1 , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Poli(ADP-Ribosa) Polimerasas/genética , ARN Interferente Pequeño/genética , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteína Elk-1 con Dominio ets/genética