Epidermal growth factor triggers an original, caspase-independent pituitary cell death with heterogeneous phenotype.
Programmed cell death (PCD) is physiologically involved in the regulation of cell division and differentiation. It encompasses caspase-dependent mitochondrial and nonmitochondrial pathways. Additional caspase-independent pathways have been characterized in mitochondrial PCDs but remain hypothetical in nonmitochondrial PCDs. Epidermal growth factor (EGF) has been shown to inhibit division of pituitary somato-lactotrope cells occurring in parallel with EGF-mediated differentiation of these precursors into lactotrope cells. We show here that in somato-lactotrope pituitary cell line GH4C1, EGF triggers a PCD characterized by an apoptosis-like DNA fragmentation, insensitivity to broad-range caspase inhibitors, and absence of either cytochrome c or apoptosis-inducing factor release from mitochondria. Dying cells display loose chromatin clustering and numerous cytoplasmic vacuoles, a fraction of which are autophagic, thus conferring a heterogeneous phenotype to this PCD. Moreover, overexpression of cell death inhibitor Bcl-2 prevented not only the EGF-induced PCD but also its prodifferentiation effects, thus pointing to a mechanistic relationship existing between these two phenomena. Overall, the characterized differentiation-linked cell death represents an original form of caspase-independent PCD. The mechanisms underlying this PCD involve combinatorial engagement of discrete death effectors leading to a heterogeneous death phenotype that might be evolutionary related to PCD seen during the differentiation of some unicellular organisms.
Fombonne
Joanna
J
Interactions Cellulaires Neuroendocriniennes, Unité Mixte de Recherche 6544, Centre National de Recherche Scientifique/Université de la Méditerranée, Institut Jean Roche, Faculté de Médecine Nord, 13916 Marseille, France.
Reix
Stéphanie
S
Rasolonjanahary
Ramahefarizo
R
Danty
Emmanuelle
E
Thirion
Sylvie
S
Laforge-Anglade
Geneviéve
G
Bosler
Olivier
O
Mehlen
Patrick
P
Enjalbert
Alain
A
Krantic
Slavica
S
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D002469:Cell Separation; D002843:Chromatin / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D053938:DNA Fragmentation; D004815:Epidermal Growth Factor / Q000378:metabolism; D005434:Flow Cytometry; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000473:pathology; D010641:Phenotype; D010902:Pituitary Gland / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014162:Transfection
D002843:Chromatin; D019253:Proto-Oncogene Proteins c-bcl-2; D004815:Epidermal Growth Factor; D045304:Cytochromes c; D020169:Caspases