PRIMA-1(MET) induces nucleolar accumulation of mutant p53 and PML nuclear body-associated proteins.
We have previously identified PRIMA-1, a low molecular weight compound that restores the transcriptional transactivation function to mutant p53 and induction of apoptosis. To explore the molecular mechanism for PRIMA-1-induced mutant p53-dependent apoptosis, we examined the intracellular distribution of mutant p53 upon treatment with PRIMA-1(MET) by immunofluorescence staining. We found that PRIMA-1(MET) induced nucleolar translocation of mutant p53 and the promyelocytic leukemia (PML) nuclear body-associated proteins PML, CBP and Hsp70. Levels of Hsp70 were significantly enhanced by PRIMA-1(MET) treatment. PRIMA-Dead, a compound structurally related to PRIMA-1 but unable to induce mutant p53-dependent apoptosis, failed to induce nucleolar translocation of mutant p53. Our results suggest that redistribution of mutant p53 to nucleoli plays a role in PRIMA-1-induced apoptosis.
Rökaeus
N
N
Department of Oncology-Pathology, Karolinska Institute, Cancer Center Karolinska (CCK), Karolinska University Hospital, Stockholm, Sweden.
Klein
G
G
Wiman
K G
KG
Szekely
L
L
Mattsson
K
K
D021581:Active Transport, Cell Nucleus; D017209:Apoptosis / Q000235:genetics; D001372:Aza Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one