Abstract
Daxx has been implicated in the modulation of apoptosis in response to various stimuli. In the nucleus, Daxx interacts and colocalizes with the promyelocytic leukemia protein (PML) into the PML-nuclear body. Moreover, overexpressed Daxx positively modulates FAS-ligand and TGFβ-induced apoptosis. However, recent reports indicate that Daxx can also act as an antiapoptotic factor. As most studies on the role of Daxx in cell death have been conducted using tumour cell lines, we analysed the function of Daxx in physiological settings. We found that Daxx is induced upon exposure to ultraviolet (UV) irradiation and hydrogen peroxide treatment. We employed RNA interference to downregulate Daxx in primary fibroblasts. Remarkably, Daxx-depleted cells are resistant to cell death induced by both UV irradiation and oxidative stress. Furthermore, the downregulation of Daxx results in impaired MKK/c-Jun-N-terminal kinase (JNK) activation. This is the first evidence that Daxx promotes cell death and JNK activation in physiological conditions.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- JNK:
-
c-Jun-N-terminal kinase
- PML:
-
promyleocytic leukaemia protein
- PML-NB:
-
PML nuclear body
- ASK1:
-
apoptosis signal regulating kinase 1
- UV:
-
ultraviolet irradiation
- RNAi:
-
RNA interference
- MAPK:
-
mitogen activated kinase
- MAPKK:
-
MAP kinase kinase
- H2O2:
-
hydrogen peroxide
- BrdU:
-
5-bromo-2′-deoxyuridine
References
Yang X, Khosravi-Far R, Chang HY and Baltimore D (1997) Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 89: 1067–1076
Chang HY, Yang X and Baltimore D (1999) Dissecting Fas signaling with an altered-specificity death-domain mutant: requirement of FADD binding for apoptosis but not Jun N-terminal kinase activation. Proc. Natl. Acad. Sci. USA 96: 1252–1256
Chang HY, Nishitoh H, Yang X, Ichijo H and Baltimore D (1998) Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Science 281: 1860–1863
Song JJ and Lee YJ (2003a) Catalase, but not MnSOD, inhibits glucose deprivation-activated ASK1-MEK-MAPK signal transduction pathway and prevents relocalization of Daxx: hydrogen peroxide as a major second messenger of metabolic oxidative stress. J. Cell. Biochem. 90: 304–314
Ishov AM, Sotnikov AG, Negorev D, Vladimirova OV, Neff N, Kamitani T, Yeh ET, Strauss III JF and Maul GG (1999) PML is critical for ND10 formation and recruits the PML-interacting protein Daxx to this nuclear structure when modified by SUMO-1. J. Cell Biol. 147: 221–234
Zhong S, Salomoni P, Ronchetti S, Guo A, Ruggero D and Pandolfi PP (2000) Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis. J. Exp. Med. 191: 631–640
Salomoni P and Pandolfi PP (2002) The role of PML in tumor suppression. Cell 108: 165–170
Torii S, Egan DA, Evans RA and Reed JC (1999) Human Daxx regulates Fas-induced apoptosis from nuclear PML oncogenic domains (PODs). EMBO J. 18: 6037–6049
Ko YG, Kang YS, Park H, Seol W, Kim J, Kim T, Park HS, Choi EJ and Kim S (2001) Apoptosis signal-regulating kinase 1 controls the proapoptotic function of death-associated protein (Daxx) in the cytoplasm. J. Biol. Chem. 276: 39103–39106
Nefkens I, Negorev DG, Ishov AM, Michaelson JS, Yeh ET, Tanguay RM, Muller WE and Maul GG (2003) Heat shock and Cd2+ exposure regulate PML and Daxx release from ND10 by independent mechanisms that modify the induction of heat–shock proteins 70 and 25 differently. J. Cell Sci. 116: 513–524
Song JJ and Lee YJ (2003b) Role of the ASK1-SEK1-JNK1-HIPK1 signal in Daxx trafficking and ASK1 oligomerization. J. Biol. Chem. 278: 47245–47252
Hollenbach AD, Sublett JE, McPherson CJ and Grosveld G (1999) The Pax3-FKHR oncoprotein is unresponsive to the Pax3-associated repressor hDaxx. EMBO J. 18: 3702–3711
Li H, Leo C, Zhu J, Wu X, O'Neil J, Park EJ and Chen JD (2000) Sequestration and inhibition of Daxx-mediated transcriptional repression by PML. Mol. Cell. Biol. 20: 1784–1796
Michaelson JS and Leder P (2003) RNAi reveals anti-apoptotic and transcriptionally repressive activities of DAXX. J. Cell Sci. 116: 345–352
Kim EJ, Park JS and Um SJ (2003) Identification of Daxx interacting with p73, one of the p53 family, and its regulation of p53 activity by competitive interaction with PML. Nucleic Acids Res. 31: 5356–5367
Hollenbach AD, McPherson CJ, Mientjes EJ, Iyengar R and Grosveld G (2002) Daxx and histone deacetylase II associate with chromatin through an interaction with core histones and the chromatin-associated protein Dek. J. Cell Sci. 115: 3319–3330
Wu S, Loke HN and Rehemtulla A (2002) Ultraviolet radiation-induced apoptosis is mediated by Daxx. Neoplasia 4: 486–492
Perlman R, Schiemann WP, Brooks MW, Lodish HF and Weinberg RA (2001) TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat. Cell Biol. 3: 708–714
Kawai T, Akira S and Reed JC (2003) ZIP kinase triggers apoptosis from nuclear PML oncogenic domains. Mol. Cell. Biol. 23: 6174–6186
Michaelson JS, Bader D, Kuo F, Kozak C and Leder P (1999) Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development. Genes Dev. 13: 1918–1923
Chen LY and Chen JD (2003) Daxx silencing sensitizes cells to multiple apoptotic pathways. Mol. Cell. Biol. 23: 7108–7121
Bissonnette N and Hunting DJ (1998) p21-induced cycle arrest in G1 protects cells from apoptosis induced by UV-irradiation or RNA polymerase II blockage. Oncogene 16: 3461–3469
Maltzman W and Czyzyk L (1984) UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol. Cell. Biol. 4: 1689–1694
Renzing J, Hansen S and Lane DP (1996) Oxidative stress is involved in the UV activation of p53. J. Cell Sci. 109 (Part 5): 1105–1112
Fridman JS and Lowe SW (2003) Control of apoptosis by p53. Oncogene 22: 9030–9040
Bendjennat M, Boulaire J, Jascur T, Brickner H, Barbier V, Sarasin A, Fotedar A and Fotedar R (2003) UV irradiation triggers ubiquitin-dependent degradation of p21(WAF1) to promote DNA repair. Cell 114: 599–610
Adams JM and Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281: 1322–1326
Woo M, Hakem R, Soengas MS, Duncan GS, Shahinian A, Kagi D, Hakem A, McCurrach M, Khoo W, Kaufman SA, Senaldi G, Howard T, Lowe SW and Mak TW (1998) Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev. 12: 806–819
Chen YR, Wang X, Templeton D, Davis RJ and Tan TH (1996) The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. J. Biol. Chem. 271: 31929–31936
Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K and Ichijo H (1998) Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 17: 2596–2606
Tobiume K, Matsuzawa A, Takahashi T, Nishitoh H, Morita K, Takeda K, Minowa O, Miyazono K, Noda T and Ichijo H (2001) ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep. 2: 222–228
Charette SJ and Landry J (2000) The interaction of HSP27 with Daxx identifies a potential regulatory role of HSP27 in Fas-induced apoptosis. Ann. N.Y. Acad. Sci. 926: 126–131
Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K and Gotoh Y (1997) Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275: 90–94
Shaulian E, Schreiber M, Piu F, Beeche M, Wagner EF and Karin M (2000) The mammalian UV response: c-Jun induction is required for exit from p53-imposed growth arrest. Cell 103: 897–907
Lei K and Davis RJ (2003) JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc. Natl. Acad. Sci. USA 100: 2432–2437
Lowe SW and Ruley HE (1993) Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. Genes Dev. 7: 535–545
Debbas M and White E (1993) Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev. 7: 546–554
Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA and Davis RJ (2000) Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288: 870–874
Tournier C, Whitmarsh AJ, Cavanagh J, Barrett T and Davis RJ (1999) The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases. Mol. Cell. Biol. 19: 1569–1581
Acknowledgements
We thank Professor H Ichijo (Tokyo Medical and Dental University, Japan) for the HA-ASK1 expression vector, Professor P Nicotera, Professor G Cohen, Dr. Marion Macfarlane, Dr. V De Laurenzi, Cristian Bellodi (MRC, Toxicology Unit, Leicester, UK), Professor G Melino (University of Rome, Tor Vergata, Italy), Dr. F Bernassola (IDI-IRCCS, University of Rome Tor Vergata, Italy) and Dr. F Condorelli (Universita’ del Piemonte Orientale, Novara, Italy) for reagents and helpful discussion. We also thank Sikand Kulvinder (MRC, Toxicology Unit, Leicester, UK) for confocal analysis. This work is supported by the Medical Research Council, UK.
Author information
Authors and Affiliations
Corresponding author
Additional information
Edited by RA Knight
Supplementary Information accompanies the paper on Cell Death and Differentiation website (http://www.nature.com/cdd)
Rights and permissions
About this article
Cite this article
Khelifi, A., D'Alcontres, M. & Salomoni, P. Daxx is required for stress-induced cell death and JNK activation. Cell Death Differ 12, 724–733 (2005). https://doi.org/10.1038/sj.cdd.4401559
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.cdd.4401559
Keywords
This article is cited by
-
Functions and dys-functions of promyelocytic leukemia protein PML
Rendiconti Lincei. Scienze Fisiche e Naturali (2018)
-
Stress-induced ceramide generation and apoptosis via the phosphorylation and activation of nSMase1 by JNK signaling
Cell Death & Differentiation (2015)
-
Subcellular localization of DAXX influence ox-LDL induced apoptosis in macrophages
Molecular Biology Reports (2014)
-
Altered PTEN, ATRX, CHGA, CHGB, and TP53 Expression Are Associated with Aggressive VHL-Associated Pancreatic Neuroendocrine Tumors
Hormones and Cancer (2013)
-
SUMO and Parkinson’s Disease
NeuroMolecular Medicine (2013)
