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.
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.
Joanna
J
Fombonne
Stéphanie
S
Reix
Ramahefarizo
R
Rasolonjanahary
Emmanuelle
E
Danty
Sylvie
S
Thirion
Geneviéve
G
Laforge-Anglade
Olivier
O
Bosler
Patrick
P
Mehlen
Alain
A
Enjalbert
Slavica
S
Krantic
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