title: p14ARF induces apoptosis via an entirely caspase-3-dependent mitochondrial amplification loop.
abstract: The p14(ARF) tumor suppressor triggers cell death or cell cycle arrest upon oncogenic stress. In MCF-7 breast carcinoma cells, expression of the tumor suppressor gene p14(ARF) fails to trigger apoptosis but induces an arrest in the G1 and, to a lesser extent, in the G2 phase in the cell division cycle. Here, inhibition of cell cycle arrest resulted in apoptosis induction in caspase-3 proficient MCF-7 cells upon expression of p14(ARF) . This occurred in the absence of S-phase progression or mitotic entry. In contrast, syngeneic, caspase-3-deficient MCF-7 cells remained entirely resistant to p14(ARF) -induced apoptosis. Thus, cell cycle checkpoint abrogation overcomes resistance to p14(ARF) -induced cell death and promotes cell death via a caspase-3-dependent pathway. Cell death coincided with dissipation of the mitochondrial membrane potential, release of cytochrome c, and was inhibitable by pan-caspase inhibitors and the caspase-3/7 inhibitor zDEVD-fmk. Of note, mitochondrial events of apoptosis execution depended entirely on caspase-3 proficiency indicating that caspase-3 either acts "up-stream" of the mitochondria in a "non-canonical" pathway or mediates a mitochondrial feedback loop to amplify the apoptotic caspase signal in p14(ARF) -induced stress signaling.
authors.affiliation: Clinical and Molecular Oncology, Max Delbrück Centrum für Molekulare Medizin, Berlin-Buch, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Milojkovic
authors.forename: Philipp G
authors.initials: PG
authors.lastname: Hemmati
authors.forename: Annika
authors.initials: A
authors.lastname: Müer
authors.forename: Tim
authors.initials: T
authors.lastname: Overkamp
authors.forename: Cindrilla
authors.initials: C
authors.lastname: Chumduri
authors.forename: Reiner U
authors.initials: RU
authors.lastname: Jänicke
authors.forename: Bernd
authors.initials: B
authors.lastname: Gillissen
authors.forename: Peter T
authors.initials: PT
authors.lastname: Daniel
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001943:Breast Neoplasms; D053148:Caspase 3 / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000378:metabolism
chemical_list: D025803:Tumor Suppressor Protein p14ARF; D053148:Caspase 3
keywords: apoptosis; caspase-3; mitochondria; p14ARF