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Molecular and Cellular Biology, October 2003, p. 7108-7121, Vol. 23, No. 20
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.20.7108-7121.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Daxx Silencing Sensitizes Cells to Multiple Apoptotic Pathways

Liuh-Yow Chen and J. Don Chen*

Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey

Received 24 March 2003/ Accepted 15 July 2003

Daxx is a nuclear protein involved in apoptosis and transcriptional repression, and it interacts with the death receptor Fas, promyelocytic leukemia protein (PML), and several transcriptional repressors. The function of Daxx in apoptosis is controversial because opposite results were obtained in transient overexpression and genetic knockout studies. Furthermore, the roles of PML and transcriptional repression in Daxx-regulated apoptosis are currently unknown. In this study, we investigated the role of Daxx in Fas- and stress-induced apoptosis by small interfering RNA-mediated Daxx silencing in mammalian cells. Daxx silencing had no apparent cytotoxic effects on mammalian cells within 72 h. Intriguingly, Daxx silencing strongly sensitized cells to Fas- and stress-induced apoptosis, which was accompanied by caspase activation, cytochrome c release, and Jun N-terminal kinase activation. Consistently, endogenous Daxx was degraded rapidly upon induction of apoptosis by stress or anti-Fas antibody. Finally, PML silencing had no effect on Daxx silencing-mediated apoptotic events, while caspase gene expression was upregulated in the absence of Daxx. These data strongly suggest that Daxx may inhibit Fas and stress-mediated apoptosis by suppressing proapoptotic gene expression outside of PML domains.

* Corresponding author. Mailing address: Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-5635. Phone: (732) 235-3292. Fax: (732) 235-3974. E-mail: chenjd{at}umdnj.edu.

Molecular and Cellular Biology, October 2003, p. 7108-7121, Vol. 23, No. 20
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.20.7108-7121.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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