The TP53 (p53) gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. The protective function of TP53 as a tumor suppressor is lost in more than 50% of human cancers. TP53 is implicated in several hereditary cancers, including Li-Fraumeni syndrome (OMIM:191170). There is a single fly ortholog, Dmel\p53, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\p53 is orthologous to two additional human genes, TP63 and TP73.
Multiple different UAS constructs of the human gene Hsap\TP53 have been introduced into flies; heterologous rescue (functional complementation) using the wild-type human gene has been demonstrated. Constructs of human Hsap\TP53 carrying variants associated with human cancers have been characterized in the fly system. Variant(s) implicated in human disease tested (as transgenic human gene, TP53): the R175H, G245S, R248Q, R273C and R273H variant forms of the human gene have been introduced into flies.
A role for TP53 in regulating transposons and other repetitive elements has been studied in mammalian systems; work using the endogenous fly gene, p53, and introduced copies of the human Hsap\TP53 gene demonstrated that both wild-type genes restrict retrotransposon activity, but mutant forms do not. In this context, the hypothesis that tumor suppression by TP53 may have been co-opted from ancestral functions that acted to contain retrotransposon activity is discussed (FBrf0230578).
Amorphic mutations in the fly p53 gene are viable, but show abnormal stress responses, including to conditions that typically induce apoptosis (reduced levels of apoptosis observed). Multiple genetic and physical interactions of Dmel\p53 have been described; see below and in the gene report for p53.
Dmel\p53 mutant animals have been used to screen drug candidates for enhancement of effects of ionizing radiation in cancer treatment.
Dmel\p53 has been found to play a role in regulated necrosis during spermatogenesis, a non-apoptotic mechanism used to control germ cell number; see the human disease model report 'cancer, multiple, regulators of necrosis' (FBhh0001067). This function is conserved in vertebrate spermatogenesis, thus raising the possibility of targeting an alternative pathway in cancers that are refractory to apoptosis.
[updated Feb. 2020 by FlyBase; FBrf0222196]
The transcription factor TP53 (p53) responds to diverse cellular stresses to regulate target genes that induce cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. In addition, TP53 appears to induce apoptosis through nontranscriptional cytoplasmic processes. In unstressed cells, TP53 is kept inactive through the actions of the ubiquitin ligase MDM2, which inhibits TP53 transcriptional activity and ubiquitinates TP53 to promote its degradation (Toledo and Wahl, 2006; pubmed:17128209). [from OMIM:191170; 2016.07.06]
The TP53 gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. [Gene Cards, TP53; 2019.06.27]