ABSTRACT
Cell extrusion is a mechanism of cell elimination that is used by organisms as diverse as sponges, nematodes, insects and mammals1-3. During extrusion, a cell detaches from a layer of surrounding cells while maintaining the continuity of that layer4. Vertebrate epithelial tissues primarily eliminate cells by extrusion, and the dysregulation of cell extrusion has been linked to epithelial diseases, including cancer1,5. The mechanisms that drive cell extrusion remain incompletely understood. Here, to analyse cell extrusion by Caenorhabditis elegans embryos3, we conducted a genome-wide RNA interference screen, identified multiple cell-cycle genes with S-phase-specific function, and performed live-imaging experiments to establish how those genes control extrusion. Extruding cells experience replication stress during S phase and activate a replication-stress response via homologues of ATR and CHK1. Preventing S-phase entry, inhibiting the replication-stress response, or allowing completion of the cell cycle blocked cell extrusion. Hydroxyurea-induced replication stress6,7 triggered ATR-CHK1- and p53-dependent cell extrusion from a mammalian epithelial monolayer. We conclude that cell extrusion induced by replication stress is conserved among animals and propose that this extrusion process is a primordial mechanism of cell elimination with a tumour-suppressive function in mammals.
Subject(s)
Caenorhabditis elegans Proteins/genetics , Cell Cycle Proteins/genetics , DNA Replication , Regulated Cell Death , S Phase , Animals , Ataxia Telangiectasia Mutated Proteins , Caenorhabditis elegans/cytology , Caenorhabditis elegans/genetics , Cell Cycle Checkpoints , Checkpoint Kinase 1 , DNA Damage , Dogs , Embryo, Nonmammalian , Gene Expression Regulation, Developmental , Madin Darby Canine Kidney Cells , RNA InterferenceABSTRACT
Insulin and insulin-like signaling regulates a broad spectrum of growth and metabolic responses to a variety of internal and environmental stimuli. For example, the inhibition of insulin-like signaling in C. elegans mediates its response to both osmotic stress and starvation. We report that in response to osmotic stress the cytosolic sulfotransferase SSU-1 antagonizes insulin-like signaling and promotes developmental arrest. Both SSU-1 and the DAF-16 FOXO transcription factor, which is activated when insulin signaling is low, are needed to drive specific responses to reduced insulin-like signaling. We demonstrate that SSU-1 functions in a single pair of sensory neurons to control intercellular signaling via the nuclear hormone receptor NHR-1 and promote both the specific transcriptional response to osmotic stress and altered lysophosphatidylcholine metabolism. Our results show the requirement of a sulfotransferase-nuclear hormone receptor neurohormonal signaling pathway for some but not all consequences of reduced insulin-like signaling.
Subject(s)
Caenorhabditis elegans/metabolism , Nerve Tissue Proteins/drug effects , Neurotransmitter Agents/metabolism , Receptor, Insulin/drug effects , Signal Transduction/drug effects , Signal Transduction/physiology , Sulfotransferases/antagonists & inhibitors , Animals , Caenorhabditis elegans Proteins/antagonists & inhibitors , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Cloning, Molecular , Embryo, Nonmammalian , Embryonic Development/genetics , Forkhead Transcription Factors/antagonists & inhibitors , Forkhead Transcription Factors/metabolism , Gene Expression Regulation, Developmental , Insulin/metabolism , Lysophosphatidylcholines/metabolism , Mutagenesis , Osmotic Pressure , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptor, Insulin/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Sensory Receptor Cells/drug effects , Starvation , Stress, Physiological , Sulfotransferases/genetics , Sulfotransferases/metabolismABSTRACT
Effect of administration of 600 mg. vitamin E each day, for six days, was observed on activity of some of the anti-oxidant enzymes and levels of malondialdehyde (as an index of free radical mediated damage) in the platelets of patients reperfused after myocardial infarction. It has been found that vitamin E administration significantly lowers the level of malondialdehyde in the patients. Vitamin E administration increases the activities of anti oxidant enzymes (viz. superoxide dismutase, glutathione reductase and catalase) tested both in the patients and healthy controls. Vitamin E administration causes general stimulation of anti-oxidant enzyme activities both in healthy persons and the patients, however, lowering of lipid per-oxidation upon administration of vitamin E is specific for patients. These findings exhibit beneficial role of vitamin E administration in the management of the patients reperfused after myocardial infarction.
