Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis.

Abstract

The low molecular weight compound PRIMA-1(MET) reactivates mutant p53 and triggers mutant p53-dependent apoptosis in human tumor cells. We investigated the effect of PRIMA-1(MET) on global gene expression using microarray analysis of Saos-2 cells expressing His273 mutant p53 and parental p53 null Saos-2 cells. PRIMA-1(MET) affected transcription of a significantly larger number of genes in the mutant p53-expressing cells compared to the p53 null cells. Genes affected by PRIMA-1(MET) in a mutant p53-dependent manner include the cell-cycle regulators GADD45B and 14-3-3gamma and the pro-apoptotic Noxa. Several of the affected genes are known p53 target genes and/or contain p53 DNA-binding motifs. We also found mutant p53-dependent disruption of the cytoskeleton, as well as transcriptional activation of the XBP1 gene and cleavage of its mRNA, a marker for endoplasmic reticulum stress. Our data show that PRIMA-1(MET) induces apoptosis through multiple transcription-dependent and -independent pathways. Such integral engagement of multiple pathways leading to apoptosis is consistent with restoration of wild-type properties to mutant p53 and is likely to reduce the risk of drug resistance development in clinical applications of PRIMA-1(MET).

• Authors: J M R Lambert, A Moshfegh, P Hainaut, K G Wiman, V J N Bykov
• Journal: Oncogene (Oncogene) Vol. 29 Issue 9 Pg. 1329-38 (Mar 04 2010) ISSN: 1476-5594 [Electronic] England
• PMID: 19946333 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Proteins
• Nerve Tissue Proteins
• PRIMA1 protein, human
• Tumor Suppressor Protein p53

Topics

• Apoptosis (physiology)
• Genes, p53 (physiology)
• Humans
• Membrane Proteins (genetics, physiology)
• Mutation
• Nerve Tissue Proteins (genetics, physiology)
• Signal Transduction (physiology)
• Tumor Suppressor Protein p53 (genetics, pharmacology)