Proteomic identification of heat shock protein 90 as a candidate target for p53 mutation reactivation by PRIMA-1 in breast cancer cells

Abstract

Introduction A loss of p53 function resulting from mutation is prevalent in human cancers. Thus, restoration of p53 function to mutant p53 using small compounds has been extensively studied for cancer therapy. We previously reported that PRIMA-1 (for 'p53 reactivation and induction of massive apoptosis') restored the transcriptional activity of p53 target genes in breast cancer cells with a p53 mutation. By using functional proteomics approach, we sought to identify molecular targets that are involved in the restoration of normal function to mutant p53.

PRIMA-1MET induces nucleolar accumulation of mutant p53 and PML nuclear body-associated proteins

“…In agreement with this idea, the inactive PRIMA-analog PRIMADead did not affect the distribution or the level of Hsp70. It is also noteworthy that a recent study has implicated Hsp90 in PRIMA-1-mediated mutant p53 reactivation (Rehman et al, 2005). However, although both Hsp70 and p53 translocate to the nucleolus, they are localized to different subnucleolar compartments.…”

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

“…An alternative mechanism could be targeting of cellular proteins that in turn bind p53 and restore its conformation and function. Indeed, PRIMA-1 induces expression of heat-shock protein 90 (Hsp90) and enhances its binding to mutant p53, suggesting that Hsp90 mediates mutant p53 refolding (Rehman et al, 2005). Moreover, PRIMA-1MET triggers redistribution of mutant p53 to nucleoli, along with three other promyelocytic leukemia protein (PML) body-associated proteins, PML, cAMPresponsive binding protein (CBP) and heat-shock protein 70 (Hsp70) (Ro¨kaeus et al, 2006).…”

Proteomics Characterization of the Molecular Mechanisms of Mutant P53 Reactivation with PRIMA-1 in Breast Cancer Cells

“…3) Part of the outcomes was published as an abstract in 2005 Era of Hope Conference (16) and as a platform presentation in the same conference (17) W81XWH-04-1-0723 …”

“…Recently, PRIMA-1 has emerged from an in vitro screen of small molecules that reactivate the transcriptional activity of mutant p53 [16]. PRIMA-1 has the capability of restoring the transcriptional transactivation function to mutant p53 in vitro and in vivo with subsequent tumor regression.…”