Characterization of EGF signaling and PYR-1 in the death of specific cells in C. elegans
Date Issued
2014
Date
2014
Author(s)
Jiang, Hang-Shiang
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. We found 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 EGF triggers apoptosis in some cell lines suggest that the EGF-mediated modulation of PCD is likely conserved in C. elegans and humans.
To identify new genes involved in PCD in C. elegans, we conducted a genetic screen for mutants with a high penetrance of tail defects in the grp-1 background. grp-1 encodes a GTP exchange factor for ARFs and mutations defective in the activation, execution, or kinetics of PCD act synergistically with the grp-1 mutation to cause abnormal tail morphology. From this screen, we isolated 182 mutants. These mutants are classified into three subgroups, depending on their cell-corpse profiles: reduced/delayed, elevated and unchanged cell corpse numbers during embryogenesis. By SNP mapping and complementation tests, 22 mutations isolated were localized in known ced genes. This result showed that this screen is feasible to identify genes important for PCD. In addition, we have isolated pyr-1, encoding C. elegans CAD (carbamoyl phosphate synthetase, aspartate transcarbamylase, and dihydroorotase). In mammals, CAD has been reported to control the rate-limiting step during pyrimidine biosynthesis. We found that pyr-1 promotes the PCD of the aunt cells of hyp8/9 and excretory cell and this cell death-promoting function is independent of its CAD activity. Moreover, we showed that PYR-1 is a substrate of CED-3 in vitro. Therefore, we identified a previously unassigned pro-apoptotic function of PYR-1.
Subjects
表皮生長因子
計畫性細胞凋亡
線蟲
SDGs
Type
thesis
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