Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

LIN-3/EGF promotes the programmed cell death of specific cells in Caenorhabditis elegans by transcriptional activation of the pro-apoptotic gene egl-1.

ABSTRACT: Programmed cell death (PCD) is the physiological death of a cell mediated by an intracellular suicide program. Although key components of the PCD execution pathway have been identified, how PCD is regulated during development is poorly understood. Here, we report that the epidermal growth factor (EGF)-like ligand LIN-3 acts as an extrinsic signal to promote the death of specific cells in Caenorhabditis elegans. The loss of LIN-3 or its receptor, LET-23, reduced the death of these cells, while excess LIN-3 or LET-23 signaling resulted in an increase in cell deaths. Our molecular and genetic data support the model that the LIN-3 signal is transduced through LET-23 to activate the LET-60/RAS-MPK-1/ERK MAPK pathway and the downstream ETS domain-containing transcription factor LIN-1. LIN-1 binds to, and activates transcription of, the key pro-apoptotic gene egl-1, which leads to the death of specific cells. Our results provide the first evidence that EGF induces PCD at the whole organism level and reveal the molecular basis for the death-promoting function of LIN-3/EGF. In addition, the level of LIN-3/EGF signaling is important for the precise fine-tuning of the life-versus-death fate. Our data and the previous cell culture studies that say EGF triggers apoptosis in some cell lines suggest that the EGF-mediated modulation of PCD is likely conserved in C. elegans and humans.

SUBMITTER: Jiang HS

PROVIDER: S-EPMC4140636 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron.

Project description:The effect of expressing human huntingtin fragments containing polyglutamine (polyQ) tracts of varying lengths was assessed in Caenorhabditis elegans ASH sensory neurons in young and old animals. Expression of a huntingtin fragment containing a polyQ tract of 150 residues (Htn-Q150) led to progressive ASH neurodegeneration but did not cause cell death. Progressive cell death and enhanced neurodegeneration were observed in ASH neurons that coexpressed Htn-Q150 and a subthreshold dose of a toxic OSM-10::green fluorescent protein (OSM-10::GFP) fusion protein. Htn-Q150 huntingtin protein fragments formed protein aggregates in ASH neurons, and the number of ASH neurons containing aggregates increased as animals aged. ASH neuronal cell death required ced-3 caspase function, indicating that the observed cell death is apoptotic. Of interest, ced-3 played a critical role in Htn-Q150-mediated neurodegeneration but not in OSM10::GFP-mediated ASH neurodegeneration. ced-3 function was important but not essential for the formation of protein aggregates. Finally, behavioral assays indicated that ASH neurons, coexpressing Htn-Q150 and OSM10::GFP, were functionally impaired at 3 days before the detection of neurodegeneration, cell death, and protein aggregates.

| S-EPMC15113 | biostudies-literature

The Caenorhabditis elegans synthetic multivulva genes prevent ras pathway activation by tightly repressing global ectopic expression of lin-3 EGF.

Project description:The Caenorhabditis elegans class A and B synthetic multivulva (synMuv) genes redundantly antagonize an EGF/Ras pathway to prevent ectopic vulval induction. We identify a class A synMuv mutation in the promoter of the lin-3 EGF gene, establishing that lin-3 is the key biological target of the class A synMuv genes in vulval development and that the repressive activities of the class A and B synMuv pathways are integrated at the level of lin-3 expression. Using FISH with single mRNA molecule resolution, we find that lin-3 EGF expression is tightly restricted to only a few tissues in wild-type animals, including the germline. In synMuv double mutants, lin-3 EGF is ectopically expressed at low levels throughout the animal. Our findings reveal that the widespread ectopic expression of a growth factor mRNA at concentrations much lower than that in the normal domain of expression can abnormally activate the Ras pathway and alter cell fates. These results suggest hypotheses for the mechanistic basis of the functional redundancy between the tumor-suppressor-like class A and B synMuv genes: the class A synMuv genes either directly or indirectly specifically repress ectopic lin-3 expression; while the class B synMuv genes might function similarly, but alternatively might act to repress lin-3 as a consequence of their role in preventing cells from adopting a germline-like fate. Analogous genes in mammals might function as tumor suppressors by preventing broad ectopic expression of EGF-like ligands.

| S-EPMC3248470 | biostudies-literature

The Lipocalin LPR-1 Cooperates with LIN-3/EGF Signaling To Maintain Narrow Tube Integrity in <i>Caenorhabditis elegans</i>.

Project description:Lipocalins are secreted cup-shaped glycoproteins that bind sterols, fatty acids, and other lipophilic molecules. Lipocalins have been implicated in a wide array of processes related to lipophilic cargo transport, sequestration, and signaling, and several are used as biomarkers for human disease, but the functions of most lipocalins remain poorly understood. Here we show that the Caenorhabditis elegans lipocalin LPR-1 is required to maintain apical membrane integrity and a continuous lumen in two narrow unicellular tubes, the excretory duct and pore, during a period of rapid lumen elongation. LPR-1 fusion protein is expressed by the duct and pore and accumulates both intracellularly and in apical extracellular compartments, but it can also function cell nonautonomously when provided from outside of the excretory system. lpr-1 mutant defects can be rescued by increased signaling through the epidermal growth factor (EGF)-Ras-extracellular signal regulated kinase (ERK) pathway, which promotes the more elongated duct vs. less elongated pore tube fate. Spatial and temporal rescue experiments indicate that Ras signaling acts within the duct and pore tubes during or prior to cell fate determination to bypass the requirement for LPR-1 lpr-1 mutations did not disrupt LIN-3/EGF-dependent duct-fate specification, prevent functioning of any specific LIN-3/EGF isoform, or alter LET-23/EGFR localization, and reduced signaling did not phenocopy or enhance lpr-1 mutant defects. These data suggest that LPR-1 protects lumen integrity through a LIN-3/EGF-independent mechanism, but that increased signaling upregulates some target(s) that can compensate for lpr-1 absence.

| S-EPMC5340336 | biostudies-literature

SPK-1, an SR protein kinase, inhibits programmed cell death in Caenorhabditis elegans.

Project description:To identify genes involved in protecting cells from programmed cell death in Caenorhabditis elegans, we performed a genetic screen to isolate mutations that cause an increase in the number of programmed cell deaths. We screened for suppressors of the cell-death defect caused by a partial loss-of-function mutation in ced-4, which encodes an Apaf-1 homolog that promotes programmed cell death by activating the caspase CED-3. We identified one extragenic ced-4 suppressor, which has a mutation in the gene spk-1. The spk-1 gene encodes a protein homologous to serine-arginine-rich (SR) protein kinases, which are thought to regulate splicing. Previous work suggests that ced-4 can be alternatively spliced and that the splice variants function oppositely, with the longer transcript (ced-4L) inhibiting programmed cell death. spk-1 might promote cell survival by increasing the amount of the protective ced-4L splice variant. We conclude that programmed cell death in C. elegans is regulated by an alternative splicing event controlled by the SR protein kinase SPK-1.

| S-EPMC3033281 | biostudies-literature

Caenorhabditis elegans genes required for the engulfment of apoptotic corpses function in the cytotoxic cell deaths induced by mutations in lin-24 and lin-33.

Project description:Two types of cell death have been studied extensively in Caenorhabditis elegans, programmed cell death and necrosis. We describe a novel type of cell death that occurs in animals containing mutations in either of two genes, lin-24 and lin-33. Gain-of-function mutations in lin-24 and lin-33 cause the inappropriate deaths of many of the Pn.p hypodermal blast cells and prevent the surviving Pn.p cells from expressing their normal developmental fates. The abnormal Pn.p cells in lin-24 and lin-33 mutant animals are morphologically distinct from the dying cells characteristic of C. elegans programmed cell deaths and necrotic cell deaths. lin-24 encodes a protein with homology to bacterial toxins. lin-33 encodes a novel protein. The cytotoxicity caused by mutation of either gene requires the function of the other. An evolutionarily conserved set of genes required for the efficient engulfment and removal of both apoptotic and necrotic cell corpses is required for the full cell-killing effect of mutant lin-24 and lin-33 genes, suggesting that engulfment promotes these cytotoxic cell deaths.

| S-EPMC2390618 | biostudies-literature

Dual-targeting pro-apoptotic peptide for programmed cancer cell death via specific mitochondria damage.

Project description:Mitochondria are vital organelles to eukaryotic cells. Damage to mitochondria will cause irreversible cell death or apoptosis. In this report, we aim at programmed cancer cell death via specific mitochondrial damage. Herein, a functionalized pro-apoptotic peptide demonstrates a dual-targeting capability using folic acid (FA) (targeting agent I) and triphenylphosphonium (TPP) cation (targeting agent II). FA is a cancer-targeting agent, which can increase the cellular uptake of the pro-apoptotic peptide via receptor-mediated endocytosis. And the TPP cation is the mitochondrial targeting agent, which specifically delivers the pro-apoptotic peptide to its particular subcellular mitochondria after internalized by cancer cells. Then the pro-apoptotic peptide accumulates in mitochondria and causes its serious damage. This dual-targeting strategy has the potential to effectively transport the pro-apoptotic peptide to targeted cancer cell mitochondria, inducing mitochondrial dysfunction and triggering the mitochondria-dependent apoptosis to efficiently eliminate cancer cells.

| S-EPMC3863817 | biostudies-other

Transcriptional control of non-apoptotic developmental cell death in C. elegans.

Project description:Programmed cell death is an essential aspect of animal development. Mutations in vertebrate genes that mediate apoptosis only mildly perturb development, suggesting that other cell death modes likely have important roles. Linker cell-type death (LCD) is a morphologically conserved cell death form operating during the development of Caenorhabditis elegans and vertebrates. We recently described a molecular network governing LCD in C. elegans, delineating a key role for the transcription factor heat-shock factor 1 (HSF-1). Although HSF-1 functions to protect cells from stress in many settings by inducing expression of protein folding chaperones, it promotes LCD by inducing expression of the conserved E2 ubiquitin-conjugating enzyme LET-70/UBE2D2, which is not induced by stress. Following whole-genome RNA interference and candidate gene screens, we identified and characterized four conserved regulators required for LCD. Here we show that two of these, NOB-1/Hox and EOR-1/PLZF, act upstream of HSF-1, in the context of Wnt signaling. A third protein, NHR-67/TLX/NR2E1, also functions upstream of HSF-1, and has a separate activity that prevents precocious expression of HSF-1 transcriptional targets. We demonstrate that the SET-16/mixed lineage leukemia 3/4 (MLL3/4) chromatin regulation complex functions at the same step or downstream of HSF-1 to control LET-70/UBE2D2 expression. Our results identify conserved proteins governing LCD, and demonstrate that transcriptional regulators influence this process at multiple levels.

| S-EPMC5136488 | biostudies-literature

Wnt signal from multiple tissues and lin-3/EGF signal from the gonad maintain vulval precursor cell competence in Caenorhabditis elegans.

Project description:The Caenorhabditis elegans vulva has been a valuable paradigm for defining components of signaling pathways and elucidating how signaling events are coordinated to generate a developmental pattern. Vulval precursor cells (VPCs) are induced to adopt vulval fates in the third larval stage by LIN-3, an EGF-like signal produced by the gonad. Competence to respond to the inductive signal requires that the VPCs do not fuse to the major hypodermal syncytium, hyp7. We found that two Wnt-encoding genes, cwn-1 and egl-20, play a major role in preventing fusion of VPCs with hyp7 in the second larval stage. By using tissue-specific rescue of mig-14/Wntless, which is required for the production of Wnt ligands, we found that Wnt signal produced by multiple tissues, including neurons and muscles, promotes or maintains VPC competence before vulval induction. In addition, through laser ablation and genetic analysis, we provide evidence that LIN-3 signal from the gonad also plays a significant role in preventing VPCs from fusing with hyp7. We propose that Wnt signaling plays a permissive role in preventing VPCs from fusing with hyp7 and reevaluate the roles of Wnt and LIN-3/EGF signaling in competence and induction.

| S-EPMC2154437 | biostudies-literature

dad-1, an endogenous programmed cell death suppressor in Caenorhabditis elegans and vertebrates.

Project description:Programmed cell death (apoptosis) is a normally occurring process used to eliminate unnecessary or potentially harmful cells in multicellular organisms. Recent studies demonstrate that the molecular control of this process is conserved phylogenetically in animals. The dad-1 gene, which encodes a novel 113 amino acid protein, was originally identified in a mutant hamster cell line (tsBN7) that undergoes apoptosis at restrictive temperature. We have identified a dad-1 homologue in Caenorhabditis elegans (Ce-dad-1) whose predicted product is > 60% identical to vertebrate DAD-1. A search of the sequence databases indicated that DAD-1-like proteins are also expressed in two plant species. Expression of either human dad-1 or Ce-dad-1 under control of a C.elegans heat-shock-inducible promoter resulted in a reduction in the number of programmed cell death corpses visible in C.elegans embryos. Extra surviving cells were present in these animals, indicating that both the human and C.elegans dad-1 genes can suppress developmentally programmed cell death. Ce-dad-1 was found to rescue mutant tsBN7 hamster cells from apoptotic death as efficiently as the vertebrate genes. These results suggest that dad-1, which is necessary for cell survival in a mammalian cell line, is sufficient to suppress some programmed cell death in C.elegans.

| S-EPMC394535 | biostudies-other

Six and Eya promote apoptosis through direct transcriptional activation of the proapoptotic BH3-only gene egl-1 in Caenorhabditis elegans.

Project description:The decision of a cell to undergo programmed cell death is tightly regulated during animal development and tissue homeostasis. Here, we show that the Caenorhabditis elegans Six family homeodomain protein C. elegans homeobox (CEH-34) and the Eyes absent ortholog EYA-1 promote the programmed cell death of a specific pharyngeal neuron, the sister of the M4 motor neuron. Loss of either ceh-34 or eya-1 function causes survival of the M4 sister cell, which normally undergoes programmed cell death. CEH-34 physically interacts with the conserved EYA domain of EYA-1 in vitro. We identify an egl-1 5' cis-regulatory element that controls the programmed cell death of the M4 sister cell and show that CEH-34 binds directly to this site. Expression of the proapoptotic gene egl-1 in the M4 sister cell requires ceh-34 and eya-1 function. We conclude that an evolutionarily conserved complex that includes CEH-34 and EYA-1 directly activates egl-1 expression through a 5' cis-regulatory element to promote the programmed cell death of the M4 sister cell. We suggest that the regulation of apoptosis by Six and Eya family members is conserved in mammals and involved in human diseases caused by mutations in Six and Eya.

| S-EPMC2932601 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data