title: 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.
authors.affiliation: Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan.
authors.forename: Hang-Shiang
authors.initials: HS
authors.lastname: Jiang
authors.affiliation: Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan; Department of Life Science, National Taiwan University, Taipei, Taiwan; Center for Systems Biology, National Taiwan University, Taipei, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan; Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Wu
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: D029742:Caenorhabditis elegans Proteins; C112486:EGL-1 protein, C elegans; C097533:Lin-1 protein, C elegans; D012097:Repressor Proteins; D014157:Transcription Factors; C075912:Lin-3 protein, C elegans; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C085873:let-23 protein, C elegans