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MBC in Press, published online ahead of print August 25, 2004
Mol. Biol. Cell 10.1091/mbc.E04-07-0601

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Submitted on July 18, 2004
Accepted on August 9, 2004

EGF Triggers an Original, Caspase-independent Pituitary Cell Death with Heterogeneous Phenotype

Joanna Fombonne,* Stéphanie Reix,* Ramahefarizo Rasolonjanahary,* Emmanuelle Danty,{dagger} Sylvie Thirion,* Geneviève Laforge-Anglade,* Olivier Bosler,* Patrick Mehlen,{dagger} Alain Enjalbert,* and Slavica Krantic*{ddagger}

*Interactions Cellulaires Neuroendocriniennes (ICNE), Unité Mixte de Recherche (UMR 6544) Centre National de Recherche Scientifique (CNRS)/Université de la Méditerranée, Institut Jean Roche, Faculté de Médecine Nord, 13916 Marseille, France; {dagger}Apoptose/Différenciation - Centre de Génétique Moléculaire et Cellulaire, Label "La Ligue" UMR 5534 CNRS/Université Claude Bernard, 69622 Villeurbanne, France

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 non-mitochondrial pathways. Additional caspase-independent pathways have been characterized in mitochondrial PCDs but remain hypothetical in non-mitochondrial 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 (AIF) release from mitochondria. Dying cells display loose chromatin clustering and numerous cytoplasmic vacuoles, a fraction of which is 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.

{ddagger}Corresponding author. E-mail: krantic.s{at}jean-roche.univ-mrs.fr




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