p53, p63 and p73 in the wonderland ofS. cerevisiae

Abstract

Since its discovery in 1979, p53 has been on the forefront of cancer research. It is considered a master gene of cancer suppression and is found mutated in around 50% of all human tumors. In addition, the progressive identification of p53-related transcription factors p63 and p73 as well as their multiple isoforms have added further layers of complexity to an already dense network. Among the numerous models used to unravel the p53 family mysteries, S. cerevisiae has been particularly useful. This seemingly naive model allows the expression of a functional human p53 and thus the assessment of p53 intrinsic transcriptional activity. The aim of this article is to review the various contributions that the budding yeast has made to the understanding of p53, p63 and p73 biology and to envision new possible directions for yeast-based assays in the field of cancer as well as other p53-family-related diseases.

Tumor suppressor protein p53 expressed in yeast can remain diffuse, form a prion, or form unstable liquid-like droplets

“…Also, overexpression of wild-type p53 could generate prion seeds de novo that, instead of providing p53 activity, cause aggregation of the p53 mutant protein causing increased loss of activity. p53 prion protein could also trap and inactivate its related transcription factors, p63 and p73 ( Billant et al., 2017 ), which could increase cancer pathology. In contrast, prion-like aggregates that do not multiply would have a more limited capacity to inactivate WT p53, p63, or p73.…”

Selective functional inhibition of a tumor-derived p53 mutant by cytosolic chaperones identified using split-YFP in budding yeast

“…Although fungi lack p53, yeast has long been an attractive system for characterizing p53 function using transcriptional reporters whose activity depends on p53 oligomerization, nuclear localization, and DNA binding (Sharma et al 2016;Billant et al 2017). Analysis using a yeast system of 76 mutants representing 54% of over 15,000 total reported missense mutations in the p53 core domain ("IARC p53 Database (p53.iarc.fr)") found that most were dominant-negative, loss-of-function alleles (Dearth et al 2007).…”

A Humanized Yeast Phenomic Model of Deoxycytidine Kinase to Predict Genetic Buffering of Nucleoside Analog Cytotoxicity

“…Informative phenomic models have been developed for multiple human diseases, including cystic fibrosis, neurodegenerative disorders, and cancer [9,282,283,284]. Molecular models include mutations in conserved residues of yeast homologs of a disease gene and introduction of human alleles into yeast.…”