ABSTRACT
The nuclear protein PARP-1 [poly(ADP-ribose) polymerase-1] is activated in cardiomyocytes exposed to hypoxia causing DNA breaks. Unlike this stress-induced PARP-1 activation, our results provide evidence for Ca(2+)-induced PARP-1 activation in contracting newborn cardiomyocytes treated with growth factors and hormones that increased their contraction rate, induced intracellular Ca(2+) mobilization and its rhythmical and transient translocation into the nucleus. Furthermore, activated PARP-1 up-regulated the activity of phosphorylated ERK (extracellular-signal-regulated kinase) in the nucleus, promoting expression of the Elk1 target gene c-fos. Up-regulation of the transcription factor c-Fos/GATA-4 promoted ANF (atrial natriuretic factor) expression. Given that expression of ANF is known to be implicated in morphological changes, growth and development of cardiomyocytes, these results outline a PARP-1-dependent signal transduction mechanism that links contraction rate and Ca(2+) mobilization with the expression of genes underlying morphological changes in cardiomyocytes.
Subject(s)
Atrial Natriuretic Factor/metabolism , Calcium/pharmacology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/enzymology , Poly(ADP-ribose) Polymerases/metabolism , Angiotensin II/pharmacology , Animals , Animals, Newborn , Atrial Natriuretic Factor/genetics , Calcium/metabolism , Enzyme Activation/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , GATA4 Transcription Factor/metabolism , Gene Expression Regulation/drug effects , Intracellular Space/drug effects , Intracellular Space/metabolism , Myocardial Contraction/drug effects , Phosphorylation/drug effects , Poly (ADP-Ribose) Polymerase-1 , Promoter Regions, Genetic/genetics , Protein Binding/drug effects , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Sprague-Dawley , Ribose/metabolismABSTRACT
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.
Subject(s)
Histones/metabolism , Mitogen-Activated Protein Kinase 1/metabolism , Poly(ADP-ribose) Polymerases/metabolism , ets-Domain Protein Elk-1/metabolism , Acetylation , Animals , Base Sequence , Brain/metabolism , Cell Nucleus/metabolism , Cell-Free System , Cells, Cultured , DNA/metabolism , Enzyme Activation , Gene Expression , Genes, fos , In Vitro Techniques , MAP Kinase Signaling System , Mitogen-Activated Protein Kinase 1/genetics , Models, Biological , Phosphorylation , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerase Inhibitors , Poly(ADP-ribose) Polymerases/genetics , RNA, Small Interfering/genetics , Rats , Rats, Sprague-Dawley , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , ets-Domain Protein Elk-1/geneticsABSTRACT
PolyADP-ribose-polymerase 1 is activated in neurons that mediate several forms of long-term memory in Aplysia. Because polyADP-ribosylation of nuclear proteins is a response to DNA damage in virtually all eukaryotic cells, it is surprising that activation of the polymerase occurs during learning and is required for long-term memory. We suggest that fast and transient decondensation of chromatin structure by polyADP-ribosylation enables the transcription needed to form long-term memory without strand breaks in DNA.
