Differential p53-Mediated Cellular Responses to DNA-Damaging Therapeutic Agents

Abstract

The gene TP53, which encodes the tumor suppressor protein p53, is mutated in about 50% of cancers. In response to cell stressors like DNA damage and after treatment with DNA-damaging therapeutic agents, p53 acts as a transcription factor to activate subsets of target genes which carry out cell fates such as apoptosis, cell cycle arrest, and DNA repair. Target gene selection by p53 is controlled by a complex regulatory network whose response varies across contexts including treatment type, cell type, and tissue type. The molecular basis of target selection across these contexts is not well understood. Knowledge gained from examining p53 regulatory network profiles across different DNA-damaging agents in different cell types and tissue types may inform logical ways to optimally manipulate the network to encourage p53-mediated tumor suppression and anti-tumor immunity in cancer patients. This may be achieved with combination therapies or with p53-reactivating targeted therapies. Here, we review the basics of the p53 regulatory network in the context of differential responses to DNA-damaging agents; discuss recent efforts to characterize differential p53 responses across treatment types, cell types, and tissue types; and examine the relevance of evaluating these responses in the tumor microenvironment. Finally, we address open questions including the potential relevance of alternative p53 transcriptional functions, p53 transcription-independent functions, and p53-independent functions in the response to DNA-damaging therapeutics.

The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer

“…Another isoform, the Δ133p53, lacking the first 132 amino acids, corresponding to the TAD I, TAD II, and the first 30 residues of the DBD, is abundant in early passage normal human fibroblasts and decreases in late passage and senescent cells ( Fujita 2019 ). Indeed, these isoforms have various MDM2-binding capacities and are expressed in a stress-dependent fashion, contributing to responses by transactivating downstream pathways ( Rozan and El-Deiry 2007 ; Allen et al 2014 ; Chen 2016 ; Haronikova et al 2019 ; Carlsen and El-Deiry 2021 ). It has been suggested that a quantitatively regulated coexpression of these distinct isoforms is required during cell proliferation ( Khoury and Bourdon 2011 ) and that the expression of different p53 isoforms is induced in response to DNA damage agents or stress to the endoplasmic reticulum ( Chen et al 2009 ).…”

Targeted Modulation of Interferon Response-Related Genes with IFN-Alpha/Lambda Inhibition

“…The p53 gene is a known suppressor of the inflammatory response, DNA damage regulator, and modulator of human TLRs gene expression [38,39]. We used p53 KO mice to assess the effect of ALOS4 treatment on inflammation caused by acute radiation [40].…”

Different Cell Responses to Hinokitiol Treatment Result in Senescence or Apoptosis in Human Osteosarcoma Cell Lines

“…Based on this finding, we tested the Furthermore, we found that the tumor suppressor p53 and its downstream gene, p21, could be activated in hinokitiol-exposed U-2 OS cells (Figure 4B). To examine the roles of p53 in hinokitiol-induced senescence, the stable Tet-on U2OS-shp53 line [15], which possesses a Tet operator-driven short hairpin RNA (shRNA) that targets p53, was applied. The results showed, in the shp53-expressing cells (with tetracycline), that the protein level of p53 was efficiently attenuated in hinokitiol-treated U-2 OS cells.…”

“…It can be activated through various stresses, including DNA damage, oncogene expression, hypoxia, and replication stress, as well as cellular metabolic changes. Once activated, p53 can trigger apoptosis, cell cycle arrest, or senescence to suppress tumor progression by activating its target genes [15,16]. CDKN1A is the critical induced gene in p53-mediated cellular senescence.…”