RGD Reference Report - Ubiquitin-dependent degradation of p53 protein despite phosphorylation at its N terminus by acetaminophen. - Rat Genome Database

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Ubiquitin-dependent degradation of p53 protein despite phosphorylation at its N terminus by acetaminophen.

Authors: Lee, YS  Wan, J  Kim, BJ  Bae, MA  Song, BJ 
Citation: Lee YS, etal., J Pharmacol Exp Ther. 2006 Apr;317(1):202-8. Epub 2005 Dec 5.
RGD ID: 2316094
Pubmed: PMID:16330492   (View Abstract at PubMed)
PMCID: PMC1409809   (View Article at PubMed Central)
DOI: DOI:10.1124/jpet.105.096719   (Journal Full-text)

We previously reported that acetaminophen (APAP, 4-hydroxyacetanilide) caused apoptosis of C6 glioma cells. Therefore, we hypothesized that the level of p53, which usually stimulates apoptosis, might be increased after APAP exposure. However, APAP exposure for 24 h markedly decreased the p53 content and its downstream target p21 in a concentration-dependent manner. Reduction of p53 was not accompanied by a decrease in p53 mRNA in C6 glioma cells, suggesting that p53 was mainly affected at the protein level. Unexpectedly, APAP stimulated phosphorylation of p53 at Ser15, Ser20, and Ser37, which usually elevates p53 content. However, phosphorylation of these residues did not prevent APAP-induced decrease in p53. The p53 reduction was independent from the level of phospho-Akt, which is known to promote p53 degradation. Immunoblot analysis of the immunoprecipitated p53 revealed that increased amounts of murine double minute 2 (mdm2) and ubiquitin were bound to p53 during its degradation. Lactacystin and N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132), inhibitors of proteasomal proteolysis, prevented the decrease, supporting the proteasomal degradation of p53 upon APAP exposure. Pretreatment with chlormethiazole, an inhibitor of ethanol-inducible CYP2E1, significantly lowered the CYP2E1 enzyme activity and the rate of APAP-induced cell death while it prevented the reduction of p53 and p21 in C6 glioma cells. A nontoxic analog of APAP, 3-hydroxyacetanilde, did not reduce p53 and p21 contents in C6 glioma cells and LLC-PK1 porcine kidney cells. Taken together, our results show that APAP or its reactive metabolite(s) can directly reduce the p53 content through mdm2-mediated ubiquitin conjugation, despite phosphorylation of p53 at its N terminus.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein ubiquitination  IMP 2316094 RGD 

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Mdm2  (MDM2 proto-oncogene)
Tp53  (tumor protein p53)


Additional Information