Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways

Abstract

The insulin/IGF-1 pathway controls a number of physiological processes in the nematode worm Caenorhabditis elegans, including development, aging and stress response. We previously found that the Akt/PKB ortholog AKT-1 dampens the apoptotic response to genotoxic stress in the germline by negatively regulating the p53-like transcription factor CEP-1. Here, we report unexpected rearrangements to the insulin/IGF-1 pathway, whereby the insulin-like receptor DAF-2 and 3-phosphoinositidedependent protein kinase PDK-1 oppose AKT-1 to promote DNA damage-induced apoptosis. While DNA damage does not affect phosphorylation at the PDK-1 site Thr350/Thr308 of AKT-1, it increased phosphorylation at Ser517/Ser473. Although ablation of daf-2 or pdk-1 completely suppressed akt-1-dependent apoptosis, the transcriptional activation of CEP-1 was unaffected, suggesting that daf-2 and pdk-1 act independently or downstream of cep-1 and akt-1. Ablation of the akt-1 paralog akt-2 or the downstream target of the insulin/IGF-1 pathway daf-16 (a FOXO transcription factor) restored sensitivity to damage-induced apoptosis in daf-2 and pdk-1 mutants. In addition, daf-2 and pdk-1 mutants have reduced levels of phospho-MPK-1/ERK in their germ cells, indicating that the insulin/IGF-1 pathway promotes Ras signaling in the germline. Ablation of the Ras effector gla-3, a negative regulator of mpk-1, restored sensitivity to apoptosis in daf-2 mutants, suggesting that gla-3 acts downstream of daf-2. In addition, the hypersensitivity of let-60/Ras gain-of-function mutants to damage-induced apoptosis was suppressed to wild-type levels by ablation of daf-2. Thus, insulin/IGF-1 signaling selectively engages AKT-2/DAF-16 to promote DNA damage-induced germ cell apoptosis downstream of CEP-1 through the Ras pathway.

Run-on of germline apoptosis promotes gonad senescence inC. elegans

“…We found that levels of PA were unaffected by daf-2(m577) but reduced by daf-2(e1370) (Supplementary Figure 7A, 7B). The observed effect of daf-2(e1370) is consistent with a previous study [39], though another report described increased germline apoptosis in daf-2(e1370) mutants [40]. Other pathways have also been shown to influence C. elegans reproductive aging, particularly TGF-β Sma/Mab signalling [18, 41, 42].…”

Developmental Coordination of Gamete Differentiation with Programmed Cell Death in Sporulating Yeast

“…Of course, an additional interpretation of our findings is that Smk1 may also participate directly in promoting PCD. Intriguingly, the MAP kinase gene mpk-1 positively regulates apoptosis-like death of immature germ cells in the syncytial Caenorhabditis elegans gonad in a phenomenon that is conceptually similar to yeast meiotic mother cell death (42,43). Further exploration of the control mechanisms by which Smk1 impacts meiotic PCD will illuminate these possibilities.…”

Effects of PLCE1 Gene Silencing by RNA Interference on Cell Cycling and Apoptosis in Esophageal Carcinoma Cells

“…Protein kinase C is an important signaling molecule in mediating tumor cell adhesion,movement,and invasion,and a PKC suppressor has displayed anti-invasion characteristics in vitro and in vivo experiments. As a special domain of PLCE1, the CDC25-like domain could change the molecular structure of Ras family via acting on guanosine triphosphate exchange factor (GEF), and activate the Ras/MAPK signaling pathways (Cui et al, 2013) and then regulate cell apoptosis and growth, promotes cell proliferation, differentiation and even malignant change (Perrin et al, 2013). Ada-Nguema AS (Ada-Nguema et al, 2006) found that phospholipase Cε (PLCε) is a novel R-Ras effector mediating the effects of R-Ras on the actin cytoskeleton and membrane protrusion, because R-Ras was coprecipitated with PLC ε and increased its activity (Martins et al, 2014).…”