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  • Original Paper
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Proteolytic regulation of Forkhead transcription factor FOXO3a by caspase-3-like proteases

Oncogene volume 22, pages 4557–4568 (2003)Cite this article

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.

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Abbreviations

AICD:

activation-induced cell death

DISC:

death-inducing signaling complex

FLIP-L:

FLICE-inhibitory protein

GFP:

green fluorescent protein

GST:

glutathione S-transferase

IL-2:

interleukin-2

NES:

nuclear export signal

NLS:

nuclear localization signal

PARP:

poly(ADP-ribose) polymerase

PI:

propidium iodide

PMA:

phorbol myristate acetate

TCR:

T-cell receptor

TM:

triple mutant

WT:

wild type

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Acknowledgements

We thank M Greenberg and J Tschopp for sharing FOXO3a vectors, FHRE-Luciferase construct and FLIP-L vector, respectively. We also thank J Blenis for providing FADD-negative and caspase-8-negative Jurkat cells. We thank Y-C Liu for 14-3-3 vectors and I Foucault for producing GST-14-3-3τ proteins. This work was supported by INSERM, and by grants from the Fondation de France, the Association pour la Recherche sur le Cancer, and the Ministère de la Recherche (ACI program). CC is a recipient of a doctoral fellowship from the Association pour la Recherche sur le Cancer.

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Authors and Affiliations

  1. INSERM U343, IFR50, Hôpital de l'Archet, Nice, Cedex 3, 06202, France

    Céline Charvet, Isabelle Alberti, Alain Bernard & Marcel Deckert

  2. INSERM U526, IFR50, Faculté de Médecine, Avenue de Valombrose, Nice, Cedex 2, 06107, France

    Frederic Luciano, Arnaud Jacquel & Patrick Auberger

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  1. Céline Charvet
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Correspondence to Marcel Deckert.

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Charvet, C., Alberti, I., Luciano, F. et al. Proteolytic regulation of Forkhead transcription factor FOXO3a by caspase-3-like proteases. Oncogene 22, 4557–4568 (2003). https://doi.org/10.1038/sj.onc.1206778

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