A novel paraptosis pathway involving LEI/L-DNaseII for EGF-induced cell death in somato-lactotrope pituitary cells.
We have recently reported that EGF triggers an original form of cell death in pituitary cell line (GH4C1) with a phenotype sharing some characteristics of both apoptosis (internucleosomal DNA fragmentation) and paraptosis (caspase-independence and cytoplasmic vacuolization). However, the endonuclease involved in EGF-induced DNA fragmentation has not been assessed so far. In the present work we therefore further explored the putative paraptosis involvement in EGF-induced cell death and asked whether L-DNaseII might be involved. Indeed, this endonuclease is known to mediate internucleosomal DNA fragmentation in caspase independent manner. Our Western blot, immunocytochemistry and enzymatic measurement assays show that EGF triggers a cleavage of Leukocyte Elastase Inhibitor (LEI) precursor into L-DNaseII, its subsequent enzymatic activation and nuclear translocation thus pointing to the involvement of this endonuclease pathway in caspase-independent DNA fragmentation. In addition, EGF-induced cell death can be blocked by paraptosis inhibitor AIP-1/Alix, but not with its anti-apoptotic C-terminal fragment (Alix-CT). Altogether these data suggest that EGF-induced cell death defines a novel, L-DNaseII-mediated form of paraptosis.
Interactions Cellulaires Neuroendocriniennes (ICNE), Unité Mixte de Recherche (UMR6544) Centre National de Recherche Scientifique (CNRS)/Université de la Méditerranée, Institut Jean Roche, Faculté de Médecine Nord 13916, Marseille, France.
J
J
Fombonne
L
L
Padrón
A
A
Enjalbert
S
S
Krantic
A
A
Torriglia
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D052682:Lactotrophs / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D010902:Pituitary Gland / Q000166:cytology; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D052683:Somatotrophs / Q000166:cytology / Q000187:drug effects* / Q000502:physiology
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C492143:Pdcd6ip protein, rat; D011498:Protein Precursors; D004815:Epidermal Growth Factor; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II; D019272:Leukocyte Elastase