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Vol. 15, Issue 11, 4938-4948, November 2004
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* 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;
Apoptose/Différenciation, Centre de Génétique Moléculaire et Cellulaire, Label "La Ligue" Unité Mixte de Recherche 5534 Centre National de Recherche Scientifique/Université Claude Bernard, 69622 Villeurbanne, France
Submitted July 18, 2004;
Accepted August 9, 2004
Monitoring Editor: Guido Guidotti
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.
Corresponding author. E-mail address: krantic.s{at}jean-roche.univ-mrs.fr.
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