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Regulation of Fas ligand expression and cell death by apoptosis-linked gene 4

Nature Medicine volume 5, pages 542–547 (1999)Cite this article

Abstract

Programmed cell death is a process required for the normal development of an organism. One of the best understood apoptotic pathways occurs in T lymphocytes and is mediated by Fas/Fas ligand (FasL) interaction. During studies of apoptosis induced by T cell-receptor engagement, we identified ALG-4F , a truncated transcript that prevents T cell-receptor-induced FasL upregulation and cell death. Overexpression of full-length ALG-4 induced transcription of FasL and, consequently, apoptosis. These results indicate that ALG-4 is necessary and sufficient for FasL expression. Fas/FasL interaction initiates cell death in many other systems, and its dysregulation is a mechanism by which several pathologic conditions arise. Understanding the molecular mechanisms of FasL regulation could be very useful in elucidating how these diseases develop and in identifying potential therapeutic targets.

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Figure 1: ALG-4F inhibits TCR-induced apoptosis.
Figure 2: ALG-4F blocks TCR-mediated FasL induction.
Figure 3: Overexpression of ALG-4 induces cell death.
Figure 4: ALG-4 overexpression induces FasL expression.
Figure 5: ALG-4 induces activation of the transcription factor NF-κB and FasL promoter expression.

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Acknowledgements

We thank T. Nagase and N. Nomura for the cDNA for human ALG-4; S.-T. Ju for the FasL reporter construct; G. Ruberti for the FasL cDNA; and M.J. Lenardo for the NF-AT and NF-κB reporter vectors. We thank F. Flomerfelt, T. Kristie and R. Schwartz for suggestions and critical reading of the manuscript, and B. Marshall for editorial assistance. E.L. is supported by a Telethon Italy fellowship grant.

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  1. T-cell Apoptosis Unit, Laboratory of Cellular and Molecular Immunology National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 4, Rm. 111, 9000 Rockville Pike , Bethesda, 20892, Maryland, USA

    Emanuela Lacana' & Luciano D'Adamio

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Correspondence to Luciano D'Adamio.

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Lacana', E., D'Adamio, L. Regulation of Fas ligand expression and cell death by apoptosis-linked gene 4. Nat Med 5, 542–547 (1999). https://doi.org/10.1038/8420

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