title: Proteolytic regulation of Forkhead transcription factor FOXO3a by caspase-3-like proteases.
abstract: Forkhead family transcription factors are critical regulators of cell cycle progression and apoptosis in hematopoietic cells. Here, we show that FOXO3a (also known as FKHRL1) is a new substrate of caspase-3-like proteases during apoptosis in T lymphocytes. FOXO3a was cleaved in vivo by caspases in leukemic Jurkat cells following engagement of Fas (CD95) receptor, staurosporine, and etoposide treatment, but not following engagement of CD99, a caspase-independent cell death inducer. Caspase-mediated cleavage of FOXO3a was also observed in CD4+ peripheral T cells subjected to activation-induced cell death. The expression of the death adapter FADD and caspase-8 was required for Fas-induced FOXO3a cleavage, but activation of survival pathways by overexpression of FLICE-inhibitory protein or phorbol myristate acetate treatment prevented it. FOXO3a was cleaved in vitro by caspase-3-like proteases at the consensus sequence DELD304A, releasing the N-terminal DNA-binding domain of FOXO3a from its C-terminal transactivating domain. Whereas full-length FOXO3a enhanced Forkhead response element-dependent transcription and apoptosis in Jurkat cells, both fragments were inactive to promote gene activation and cell death. In contrast, a caspase-resistant FOXO3a mutant exhibited enhanced transcriptional and proapoptotic activities. Together, these results indicate that the proteolytic cleavage of FOXO3a by caspases may represent a novel regulatory mechanism of FOXO3a activity during death receptors signaling.
authors.affiliation: INSERM U343, IFR50, Hôpital de l'Archet, 06202 Nice, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Charvet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Alberti
authors.forename: Frederic
authors.initials: F
authors.lastname: Luciano
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquel
authors.forename: Alain
authors.initials: A
authors.lastname: Bernard
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
authors.forename: Marcel
authors.initials: M
authors.lastname: Deckert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001665:Binding Sites; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017124:Conserved Sequence; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology; D053200:Fas-Associated Death Domain Protein; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019311:Staurosporine / Q000494:pharmacology; D013347:Subcellular Fractions; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D019014:fas Receptor / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; C505533:FADD protein, human; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D053200:Fas-Associated Death Domain Protein; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D014157:Transcription Factors; D019014:fas Receptor; D005047:Etoposide; D004247:DNA; D010450:Endopeptidases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate