RGD Reference Report - Modulation of poly(ADP-ribose) polymerase-1 (PARP-1)-mediated oxidative cell injury by ring finger protein 146 (RNF146) in cardiac myocytes. - Rat Genome Database

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Modulation of poly(ADP-ribose) polymerase-1 (PARP-1)-mediated oxidative cell injury by ring finger protein 146 (RNF146) in cardiac myocytes.

Authors: Gerö, Domokos  Szoleczky, Petra  Chatzianastasiou, Athanasia  Papapetropoulos, Andreas  Szabo, Csaba 
Citation: Gerö D, etal., Mol Med. 2014 Jul 31;20:313-28. doi: 10.2119/molmed.2014.00102.
RGD ID: 13524867
Pubmed: PMID:24842055   (View Abstract at PubMed)
PMCID: PMC4153837   (View Article at PubMed Central)
DOI: DOI:10.2119/molmed.2014.00102   (Journal Full-text)

Poly(ADP-ribose) polymerase-1 (PARP-1) activation is a hallmark of oxidative stress-induced cellular injury that can lead to energetic failure and necrotic cell death via depleting the cellular nicotinamide adenine dinucleotide (NAD(+)) and ATP pools. Pharmacological PARP-1 inhibition or genetic PARP-1 deficiency exert protective effects in multiple models of cardiomyocyte injury. However, the connection between nuclear PARP-1 activation and depletion of the cytoplasmic and mitochondrial energy pools is poorly understood. By using cultured rat cardiomyocytes, here we report that ring finger protein 146 (RNF146), a cytoplasmic E3-ubiquitin ligase, acts as a direct interactor of PARP-1. Overexpression of RNF146 exerts protection against oxidant-induced cell death, whereas PARP-1-mediated cellular injury is augmented after RNF146 silencing. RNF146 translocates to the nucleus upon PARP-1 activation, triggering the exit of PARP-1 from the nucleus, followed by rapid degradation of both proteins. PARP-1 and RNF146 degradation occurs in the early phase of myocardial ischemia-reperfusion injury; it precedes the induction of heat shock protein expression. Taken together, PARP-1 release from the nucleus and its rapid degradation represent newly identified steps of the necrotic cell death program induced by oxidative stress. These steps are controlled by the ubiquitin-proteasome pathway protein RNF146. The current results shed new light on the mechanism of necrotic cell death. RNF146 may represent a distinct target for experimental therapeutic intervention of oxidant-mediated cardiac injury.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Rnf146Ratcellular response to hydrogen peroxide  IMP  RGD 
Rnf146Ratnegative regulation of cellular response to oxidative stress  IMP hydrogen peroxide-induced cardiomyocyte deathRGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Rnf146Ratenzyme binding  IPIParp1 (Rattus norvegicus) RGD 
Parp1Ratubiquitin protein ligase binding  IPIRnf146 (Rattus norvegicus) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Parp1  (poly (ADP-ribose) polymerase 1)
Rnf146  (ring finger protein 146)


Additional Information