The TP53 signaling network in mammals and worms

Abstract

The nematode worm Caenorhabditis elegans has been an invaluable model organism for studying the molecular mechanisms that govern cell fate, from fundamental aspects of multicellular development to programmed cell death (apoptosis). The transparency of this organism permits visualization of cells in living animals at high resolution. The powerful genetics and functional genomics tools available in C. elegans allow for detailed analysis of gene function, including genes that are frequently deregulated in human diseases such as cancer. The TP53 protein is a critical suppressor of tumor formation in vertebrates, and the TP53 gene is mutated in over 50% of human cancers. TP53 suppresses malignancy by integrating a variety of cellular stresses that direct it to activate transcription of genes that help to repair the damage or trigger apoptotic death if the damage is beyond repair. The TP53 paralogs, TP63 and TP73, have distinct roles in development as well as overlapping functions with TP53 in apoptosis and repair, which complicates their analysis in vertebrates. C. elegans contains a single TP53 family member, cep-1, that shares properties of all three vertebrate genes and thus offers a simple system in which to study the biological functions of this important gene family. This review summarizes major advances in our understanding of the TP53 family using C. elegans as a model organism.

Mutation of a Nopp140 gene dao-5 alters rDNA transcription and increases germ cell apoptosis in C. elegans

“…46 In this study with the C. elegans model, we provided evidence that both CEP-1 target genes, egl-1 and ced-13 , each encoding a key activator of apoptosis, would be transactivated in the absence of DAO-5 as shown in other stresses, such as genotoxic response (Figure 6). 37, 38, 39 Thus, the higher apoptotic rate found in the absence of DAO-5 (Figure 3d) seems to be conserved with the TCS murine model. Although the underlying CEP-1/p53-triggering mechanism in the absence of DAO-5/CeNopp140 remains obscure, the increase in apoptosis may serve as a protective surveillance in C. elegans gonad to prevent the nonqualified germ cells from giving rise to oocytes.…”

“…1 Previously, in C. elegans , several lines of evidence showed that the disrupted ribosomal biogenesis or depletion of nucleolar proteins would induce CEP-1 (the C. elegans p53 homolog) activity to enhance defensive or protective mechanisms in the organism. 35, 36 To examine whether loss of DAO-5 would also elicit a higher CEP-1 activity, we first performed reverse transcription-quantitative PCR (RT-qPCR) to determine the abundance of egl-1 and ced-13 transcripts, 37, 38, 39 both CEP-1 downstream target genes whose induction are regarded as CEP-1 activation, in N2 and dao-5 ( ok542 ) animals. The amounts of egl-1 and ced-13 transcripts were 2- to 6-fold higher in dao-5 ( ok542 ) worms compared with N2 (Figure 6a).…”

Stress-Induced Sleep After Exposure to Ultraviolet Light Is Promoted by p53 inCaenorhabditis elegans

“…A lack of proteostatic stress following UVC irradiation led us to look at genes involved in genotoxic stress, namely ATL-1 (C. elegans homolog of mammalian ATR) and CEP-1 (C. elegans homolog of P53 family). ATL-1, along with the 9-1-1 complex (HPR-9, MRT-2, and HUS-1) detects DNA lesions induced by UVC irradiation and then activates CEP-1, which in turn activates a proapoptosis transcriptional program in the germline (Jolliffe and Derry 2013). Our results show that CEP-1 is functioning to promote UVC-induced quiescence.…”

“…These behaviors occur during UV irradiation but little is known about how the animal behaves during recovery from UV exposure. The cellular response to UV irradiation in C. elegans is homologous to the mammalian DNA damage repair pathway and includes homologs of DNA surveillance protein ataxia telangiectasia and RAD3related kinase (ATR) and the tumor suppressor p53 (Jolliffe and Derry 2013). In this study we describe sleep behavior during recovery from UV irradiation.…”

Serum microRNAs as potential biomarkers of mandibular prognathism

“…Genes targeted by let‐7i are found associated with the regulation of tissue growth and apoptosis. TP53, a popular gene, is associated with the repair of cell damage or with triggering apoptotic death if the damage is beyond repair (Jolliffe and Derry, ), while the dysfunction of programmed cell death can cause the eventual overgrowth of mandibular bone. The above reasoning may explain why the two miRNAs are expressed differentially from the gene level and indicate related genes to be explored by further research.…”