The transcription-independent mitochondrial cell death pathway is defective in non-transformed cells containing the Pro47Ser variant of p53. Issue 11 (2nd November 2018)

• Record Type: Journal Article
• Authors: Budina-Kolomets, Anna; Barnoud, Thibaut; Murphy, Maureen E.
• Is Part Of: Cancer biology & therapy. Volume 19:Issue 11(2018)
• Page Start: 1033
• Page End: 1038
• Publication Date: 2018-11-02
• Subjects: p53 -- polymorphism -- Pro47Ser -- mitochondria -- PIN1; 616.99406
• DOI: 10.1080/15384047.2018.1472194
• Languages: English
• ISSNs: 1538-4047

Abstract

ABSTRACT: Approximately half of all human cancers contain mutations in the TP53 tumor suppressor. In addition to mutations, there are single nucleotide polymorphisms (SNPs) in TP53 that can dampen p53 function, and can increase cancer risk and decrease the efficacy of cancer therapy. Approximately 6% of Africans and 1% of African-Americans express a p53 allele with a serine instead of proline at position 47 (Pro47Ser, or S47). The S47 variant is associated with increased breast cancer risk in pre-menopausal African Americans, and in a mouse model for the S47 variant, mice are predisposed to spontaneous cancers. We recently showed that the S47 variant is impaired for p53-mediated apoptosis in response to radiation and some genotoxic agents, particularly cisplatin. Here we identify the mechanism for impaired apoptosis of S47 in response to cisplatin. We show that following cisplatin treatment, the S47 variant shows normal stabilization and serine 15 phosphorylation, but reduced ability to bind to the peptidyl prolyl isomerase PIN1, which controls the mitochondrial localization of p53. This is accompanied by impaired mitochondrial localization of S47, along with decreased induction of cleaved caspase-3. Interestingly, we show that this defect occurs only for cisplatin and not for camptothecin. These findings show that normal tissues may respond differently to genotoxic stress depending upon this TP53 genotype. These data suggest that toxicity to cisplatin may be decreased in S47 individuals, and that this compound may be a superior treatment option for these individuals.