Epidermal growth factor triggers an original, caspase-independent pituitary cell death with heterogeneous phenotype.

authors

• Fombonne Joanna
• Reix Stépanie
• Rasolonjanahary Ramahefarizo
• Danty Emmanuelle
• Thirion Sylvie
• Laforge-Anglade Geneviève
• Bosler Olivier
• Mehlen Patrick
• Enjalbert Alain
• Krantic Slavica

keywords

• Western immunoblotting
• Cell separation
• Chromatin
• Pituitary gland

abstract

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.

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