An Essential Role for Daxx in the Inhibition of B Lymphopoiesis by Type I Interferons

Góngora, Rafael; Stephan, Robert P.; Zhang, Zhixin; Cooper, Max D.

doi:10.1016/s1074-7613(01)00152-2

Cited by 90 publications

(81 citation statements)

References 53 publications

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“…Since DAXX also resides in the NB (Ishov et al, 1999) and interacts with ETS1 (Li et al, 2000b), we also determined if DAXX is induced by IFNa. Although it has been shown that DAXX is induced by type I interferons in lymphoid cells (Gongora et al, 2001), we did not detect any change in expression of DAXX in response to IFN-a treatment in the epithelial cell lines tested (Figure 3b). …”

Section: Ets1 Alters Sp100 Nuclear Body Morphologycontrasting

confidence: 60%

SP100 expression modulates ETS1 transcriptional activity and inhibits cell invasion

Yordy

Sementchenko

et al. 2004

Oncogene

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The ETS1 transcription factor is a member of the Ets family of conserved sequence-specific DNA-binding proteins. ETS1 has been shown to play important roles in various cellular processes such as proliferation, differentiation, lymphoid development, motility, invasion and angiogenesis. These diverse roles of ETS1 are likely to be dependent on specific protein interactions. To identify proteins that interact with ETS1, a yeast two-hybrid screen was conducted. Here, we describe the functional interaction between SP100 and ETS1. SP100 protein interacts with ETS1 both in vitro and in vivo. SP100 is localized to nuclear bodies and ETS1 expression alters the nuclear body morphology in living cells. SP100 negatively modulates ETS1 transcriptional activation of the MMP1 and uPA promoters in a dose-dependent manner, decreases the expression of these endogenous genes, and reduces ETS1 DNA binding. Expression of SP100 inhibits the invasion of breast cancer cells and is induced by Interferon-a, which has been shown to inhibit the invasion of cancer cells. These data demonstrate that SP100 modulates ETS1-dependent biological processes.

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Section: Ets1 Alters Sp100 Nuclear Body Morphologycontrasting

confidence: 60%

SP100 expression modulates ETS1 transcriptional activity and inhibits cell invasion

Yordy

Sementchenko

et al. 2004

Oncogene

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“…[100][101][102][103] The protein was originally identified by its interaction with the intracellular domain of CD95 in a yeast two-hybrid screen and described to act as an adaptor protein that activates the MAP3K apoptosis signal-regulating kinase 1 (ASK1) and triggers the activation of the JNK signalling pathway and apoptosis. 100,101 A recent report suggests that the CD95-Daxx-ASK1 signalling route in particular operates in a cell type-specific manner during apoptosis of motoneurons.…”

Section: Daxxmentioning

confidence: 99%

“…In addition, a proapoptotic function of Daxx has also been found in human B progenitor cells, where Daxx is upregulated by interferon treatment and regulates lymphopoiesis through downregulation of the antiapoptotic regulator Bcl-2 followed by the induction of apoptosis. 103 In contrast to its proapoptotic functions, Daxx also exerts an antiapoptotic function during embryogenesis. 115 Moreover, recent work using siRNA-mediated downregulation of Daxx also demonstrated an antiapoptotic function of Daxx in different cell lines, demonstrating that this effect is not just restricted to embryonic development.…”

Section: Daxxmentioning

confidence: 99%

Body language: the function of PML nuclear bodies in apoptosis regulation

2003

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Promyelocytic leukaemia (PML) nuclear bodies (NBs) are macromolecular nuclear domains present in virtually every mammalian cell. PML nuclear bodies (PML-NBs) were functionally linked to various fundamental cellular processes, including transcriptional control, tumour suppression and apoptosis regulation. Supporting the important function of PML and its associated NBs in apoptosis regulation, several apoptotic regulators localise to PML-NBs, and cells from PMLdeficient mice show severe apoptotic defects, including induction of genotoxic stress and death receptor CD95 (Fas/ APO-1) activation. Based on the current literature, we hypothesise that PML-NBs regulate apoptosis through different molecular mechanisms, on the one hand by acting as macromolecular scaffolds for recruitment and post-translational modification of the apoptotic key regulator p53, and on the other by regulating the subcellular bioavailability and quality of some apoptotic signal transducers.

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“…Subsequent studies implicate Daxx in promoting apoptosis in diverse stress conditions (12)(13)(14)(15). Paradoxically, homozygous deletion of the Daxx gene in mice results in embryonic lethality and widespread apoptosis was observed in Daxx-deficient embryos and cells (16), indicating that Daxx has anti-apoptotic function and is critical for organismal development.…”

mentioning

confidence: 99%

Negative Regulation of p53 Functions by Daxx and the Involvement of MDM2

Zhao

Liu

Sidhu

et al. 2004

Journal of Biological Chemistry

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In normal cells p53 activity is tightly controlled and MDM2 is a known negative regulator. Here we show that via its acidic domain, Daxx binds to the COOH-terminal domain of p53, whose positive charges are critical for this interaction, as Lys to Arg mutations preserved, but Lys to Ala or Ser to Glu mutations abolished Daxx-p53 interaction. These results thus implicate acetylation and phosphorylation of p53 in regulating its binding to Daxx. Interestingly, whereas Daxx did not bind to p53 in cells as assessed by immunoprecipitation, MDM2 expression restored p53-Daxx interaction, and this correlated with deacetylation of p53. In p53/MDM2-null mouse embryonic fibroblasts (DKO MEF), Daxx repressed p53 target promoters whose p53-binding elements were required for the repression. Coexpression of Daxx and MDM2 led to further repression. p53 expression in DKO MEF induced apoptosis and Daxx expression relieved this effect. Similarly, in HCT116 cells, Daxx conferred striking resistance to 5-fluorouracil-induced apoptosis. As p53 is required for 5-fluorouracil-induced cell death, our data show that Daxx can suppress cell death induced by p53 overexpression and p53-dependent stress response. Collectively, our data reveal Daxx as a novel negative regulator of p53. Importantly, posttranslational modifications of p53 inhibit Daxx-p53 interaction, thereby relieving negative regulation of p53 by Daxx.The critical role of p53 in tumor suppression is manifested in frequent mutations of the p53 gene in cancers (ϳ50% of all human cancers) and in its inactivation in many other cancers by cellular or viral oncogenes and other epigenetic alterations (1). p53-deficient mice develop normally, although such mice exhibit higher incidence of tumors than their wild-type counterparts, demonstrating a critical role for p53 in suppressing tumors (2). p53 exerts its tumor suppression function by activating expression of genes involved in growth arrest and apoptosis (3, 4), and it can also induce apoptosis directly by binding to Bcl-2 family proteins and triggering cytochrome c release (5). Inducing growth arrest and cell death by p53 can impact negatively on normal cell growth and organismal development. Indeed, deletion of the mdm2 gene, whose product is a negative regulator of p53, results in embryonic lethality, but deletion of both p53 and mdm2 simultaneously completely rescues such lethal phenotype (6, 7). Thus, p53 activity must be tightly controlled under physiological conditions. In addition to MDM2, numerous cellular and viral proteins interact with p53 and these proteins can positively or negatively modulate p53-mediated biological effects. Recently, we and others demonstrated that the transcriptional corepressor Daxx interacts with p53 (8 -10), but the biological significance of this interaction remains to be explored.Daxx was initially identified as a binding protein of Fas death domain and was shown to potentiate Fas-mediated apoptosis (11). Subsequent studies implicate Daxx in promoting apoptosis in diverse stress conditions (12-1...

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An Essential Role for Daxx in the Inhibition of B Lymphopoiesis by Type I Interferons

Cited by 90 publications

References 53 publications

SP100 expression modulates ETS1 transcriptional activity and inhibits cell invasion

SP100 expression modulates ETS1 transcriptional activity and inhibits cell invasion

Body language: the function of PML nuclear bodies in apoptosis regulation

Negative Regulation of p53 Functions by Daxx and the Involvement of MDM2

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