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First published online 27 November 2002
doi: 10.1242/jcs.00234

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Journal of Cell Science 116, 345-352 (2003)
doi: 10.1242/jcs.00234

Research Article

RNAi reveals anti-apoptotic and transcriptionally repressive activities of DAXX

Jennifer S. Michaelson* and Philip Leder{ddagger}

Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
* Present address: Department of Exploratory Science, Biogen Inc., 12 Cambridge Center, Cambridge, Massachusetts 02142, USA

{ddagger} Author for correspondence (e-mail: leder{at}rascal.med.harvard.edu)

Accepted 23 October 2002

The function of DAXX, a highly conserved mammalian gene, has remained controversial; this is due, in part, to its identification in a variety of yeast two-hybrid screens. Targeted deletion in the mouse revealed that DAXX is essential for embryonic development. Furthermore, the increased levels of apoptosis observed in Daxx-knockout embryos and embryonic stem cell lines suggested that DAXX functions in an anti-apoptotic capacity. In contrast, overexpression studies showed that DAXX may promote apoptosis. Additional studies showed that, when overexpressed, DAXX could function as a transcriptional repressor. To clarify these matters, we have used RNAi to deplete endogenous DAXX and thereby assess DAXX function in cell lines previously tested in overexpression studies. Increased apoptosis was observed in DAXX-depleted cells, showing DAXX to be anti-apoptotic. The apoptosis induced by the absence of DAXX was rescued by Bcl-2 overexpression. In addition, transcriptional derepression was observed in RNAi-treated cells, indicating the ability of endogenous DAXX to repress gene expression and allowing for the identification of novel targets of DAXX repression, including nuclear factor {kappa}B (NF-{kappa}B)- and E2F1- regulated targets. Thus, depletion of DAXX by RNAi has verified the crucial role of endogenous DAXX as an anti-apoptotic regulator, and has allowed the identification of probable physiological targets of DAXX transcriptional repression.

Key words: DAXX, RNAi, Apoptosis, Transcriptional repression, NF-{kappa}B, E2F1


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DAXX: apoptotic or anti-apoptotic?

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