Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD43 (leukosialin, sialophorin), an abundant leukocyte surface sialoglycoprotein, regulates leukocyte adhesion and transmits activating signals in T cells and dendritic cells. Immobilized anti-CD43 monoclonal antibody (mAb) MEM-59 has been previously shown to induce apoptosis of hematopoietic progenitors. In this study we show that it also triggers apoptosis of the myeloid progenitor-derived cell line TF-1. The kinetics of the MEM-59-induced apoptosis were unusually slow, with the first apoptotic cells appearing 36-48 h after their contact with the immobilized antibody; in 5 days, 90% of the cells were dead. CD43-mediated apoptosis was enhanced by coimmobilized anti-CD45 mAb and partly suppressed by coimmobilized anti-CD50 (ICAM-3) or anti-CD99 mAb. The MEM-59-triggered apoptosis of TF-1 cells was also inhibited by the overexpression of an apoptotic regulator, Daxx. CD43-mediated apoptosis was preceded by the repression of the DNA binding activity of the transcription factor AP-1. DNA array screening revealed that the expression of several genes encoding apoptosis-regulating proteins, including 14-3-3 proteins and the granulocyte macrophage colony-stimulating factor (GM-CSF) receptor beta-subunit, was repressed in TF-1 cells bound to immobilized MEM-59. The down-regulation of 14-3-3 proteins and GM-CSF receptor beta was accompanied by translocation of the proapoptotic protein Bad to the mitochondria. These results suggest that engagement of CD43 may, presumably through the repressing transcription, initiate a Bad-dependent apoptotic pathway.
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PMID:Molecular mechanisms involved in CD43-mediated apoptosis of TF-1 cells. Roles of transcription Daxx expression, and adhesion molecules. 1177 67

UV irradiation and other stress-activated signals activate the Jun N-terminal kinase (JNK, SAPK) pathway. The induction of JNK activity results in the activation of proto-oncogene c-Jun and activator protein-1 (AP-1) transcriptional activity. Data presented here show that UV mediated the activation of JNK correlated with UV-induced apoptosis and that overexpression of a dominant negative JNK blocked UV-induced apoptosis. However, the molecular events that lead to JNK activation in response to UV treatment are not clear. In this report, we provide evidence that a Fas receptor binding protein, Daxx, mediates UV-induced JNK activation and apoptosis. A dominant negative Daxx, coding for the C-terminal region (112 amino acids) of Daxx, was constructed and used in the experiments. Our data show that overexpression of the dominant negative Daxx partially inhibits UV-induced JNK phosphorylation in 293 cells. Inhibition of JNK phosphorylation resulted in the inhibition of c-Jun activation upon UV irradiation. Our data also show that the inhibition of JNK activation by dominant negative Daxx correlates with the reduced rate of apoptotic death of 293 cells after UV irradiation. Surprisingly, overexpression of wild-type Daxx also inhibited UV-induced apoptosis, suggesting that Daxx competes for Fas receptor binding sites with other proapoptotic factors such as FADD. In addition, overexpression of a dominant negative mutant of FADD did not affect UV-induced JNK activation but does inhibit UV-induced apoptosis. These results suggest that UV-induced JNK activation is not sufficient but required for induction of apoptosis.
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PMID:Ultraviolet radiation-induced apoptosis is mediated by Daxx. 1240 42

During a screen to identify c-Jun activators, we isolated a cysteine protease, SuPr-1, that induced c-Jun-dependent transcription independently of c-Jun phosphorylation. SuPr-1 is a member of a new family of proteases that hydrolyze the ubiquitin-like modifier, SUMO-1. SuPr-1 hydrolyzed SUMO-1-modified forms of the promyelocytic leukemia gene product, PML, and altered the subcellular distribution of PML in nuclear PODs (PML oncogenic domains). SuPr-1 also altered the distribution of other nuclear POD-associated proteins, such as CBP and Daxx, that act as transcriptional regulators. SuPr-1 action on transcription was enhanced by PML, and SuPr-1 failed to activate transcription in PML-deficient fibroblasts. Our studies establish an important role for SUMO proteases in transcription.
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PMID:SUMO-1 protease-1 regulates gene transcription through PML. 1241 28

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine/threonine kinase involved in transcriptional regulation and apoptosis. Here we demonstrate that HIPK2 regulates transforming growth factor (TGF) beta-induced c-Jun NH(2)-terminal kinase (JNK) activation and apoptosis. HIPK2 colocalizes with Daxx, a protein acting in TGF-beta-induced JNK activation and apoptosis, in promyelocytic leukemia (PML) nuclear bodies, and triggers PML-nuclear body disruption and release of Daxx. HIPK2 interacts in vitro and in vivo via its kinase domain with Daxx, and a fraction of Daxx coprecipitates with HIPK2 under physiological conditions. Moreover, overexpression of HIPK2 leads to Daxx phosphorylation, and ectopic expression of HIPK2 activates the JNK signaling pathway, which is enhanced by coexpression of Daxx. HIPK2 signals to JNK via a pathway using Daxx and the mitogen-activated protein kinase kinases MKK4/SEK1 and MKK7. Ectopic expression of HIPK2 and Daxx potentiates TGF-beta-induced apoptosis in human p53-deficient hepatocellular carcinoma cells. Finally, we demonstrate that knockdown of endogenous HIPK2 using RNA interference inhibits TGF-beta-induced JNK activation and apoptosis. Taken together, our findings indicate that HIPK2 participates in the TGF-beta signaling pathway leading to JNK activation and apoptosis.
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PMID:HIPK2 regulates transforming growth factor-beta-induced c-Jun NH(2)-terminal kinase activation and apoptosis in human hepatoma cells. 1467 85

Ubc9 is an E2-conjugating enzyme required for sumoylation and has been implicated in regulating several critical cellular pathways. We have shown previously that Ubc9 is important for sumoylation and nucleolar delocalization of topoisomerase (topo) I in response to topo I inhibitors such as topotecan. However, the role for Ubc9 in tumor drug responsiveness is not clear. In this study, we found that although MCF7 cells expressing a Ubc9 dominant-negative mutant (Ubc9-DN) display decreased activity of topo I, these cells are more sensitive to the topo I inhibitor topotecan and other anticancer agents such as VM-26 and cisplatin. In addition, we found that alteration of Ubc9 expression correlates with drug responsiveness in tumor cell lines. To understand possible mechanisms of Ubc9-associated drug responsiveness, we examined several proteins that have been shown to interact with Ubc9 and that may be involved in drug responsiveness. One such protein is Daxx, which is a Fas-associated protein that plays a role in Fas-mediated apoptosis by participating in a caspase-independent pathway through activation of apoptosis signal-regulating kinase 1 and c-Jun NH(2)-terminal kinase. We found that cells expressing Ubc9-DN accumulate more cytoplasmic Daxx than the control cells. Because cytoplasmic Daxx is believed to participate in cellular apoptosis, we suggest that the interaction of Ubc9 with Daxx and subsequent alteration in the subcellular localization of Daxx may contribute to the increased sensitivity to anticancer drugs in the cells expressing Ubc9-DN. Finally, we found that overexpression of Daxx sensitizes cells to anticancer drugs possibly in part through alterations of the ratio of cytoplasmic and nuclear Daxx. Together, our results suggest a role for Ubc9 in tumor drug responsiveness.
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PMID:Overexpression of a dominant-negative mutant Ubc9 is associated with increased sensitivity to anticancer drugs. 1508 95

Death-associated protein (Daxx) deletion mutant (aa 501-625) has been known to be an inducer of apoptosis. In this study, we observed that the Bax-dependent mitochondrial death signaling pathway plays an important role in Daxx501-625-induced apoptosis. Daxx fragment-induced activation of caspase-9 and -3 was mediated through the apoptosis signal-regulating kinase 1 (ASK1)-MEK-c-Jun-N-terminal kinase (JNK)/p38-Bax pathway. By overexpressing JNK-binding domain (JBD) of JIP1, a JNK-inhibitory protein, and treatment with SB203580, a specific p38 inhibitor, DU-145 cells were made resistant to Daxx501-625-induced apoptosis. Capase-3 deficiency, Bax deficiency, or overexpression of a dominant-negative caspase-9 mutant prevented apoptosis, even though the Daxx501-625 fragment still activated the ASK1-MEK-MAPK pathway. Interestingly, Daxx501-625-induced Bcl-2 interacting domain (Bid) cleavage was suppressed in the dominant-negative caspase-9 mutant cells, whereas Bim was still phosphorylated in these cells. These results suggest that cleavage of Bid occurs downstream of caspase-9 activation. In contrast, phosphorylation of Bim is upstream of caspase-9 activation. Taken together, our results suggest that Daxx501-625-induced apoptosis is mediated through the ASK1-MEK-JNK/p38-Bim-Bax-dependent caspase pathway.
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PMID:Daxx deletion mutant (amino acids 501-625)-induced apoptosis occurs through the JNK/p38-Bax-dependent mitochondrial pathway. 1525 8

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 TGFbeta-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.
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PMID:Daxx is required for stress-induced cell death and JNK activation. 1586 Nov 94

We have previously observed that metabolic oxidative stress-induced death domain-associated protein (Daxx) trafficking is mediated by the ASK1-SEK1-JNK1-HIPK1 signal transduction pathway. The relocalized Daxx from the nucleus to the cytoplasm during glucose deprivation participates in a positive regulatory feedback loop by binding to apoptosis signal-regulating kinase (ASK) 1. In this study, we report that Akt1 is involved in a negative regulatory feedback loop during glucose deprivation. Akt1 interacts with c-Jun NH(2)-terminal kinase (JNK)-interacting protein (JIP) 1, and Akt1 catalytic activity is inhibited. The JNK2-mediated phosphorylation of JIP1 results in the dissociation of Akt1 from JIP1 and subsequently restores Akt1 enzyme activity. Concomitantly, Akt1 interacts with stress-activated protein kinase/extracellular signal-regulated kinase (SEK) 1 (also known as MKK4) and inhibits SEK1 activity. Knockdown of SEK1 leads to the inhibition of JNK activation, JIP1-JNK2 binding, and the dissociation of Akt1 from JIP1 during glucose deprivation. Knockdown of JIP1 also leads to the inhibition of JNK activation, whereas the knockdown of Akt1 promotes JNK activation during glucose deprivation. Altogether, our data demonstrate that Akt1 participates in a negative regulatory feedback loop by interacting with the JIP1 scaffold protein.
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PMID:Dissociation of Akt1 from its negative regulator JIP1 is mediated through the ASK1-MEK-JNK signal transduction pathway during metabolic oxidative stress: a negative feedback loop. 1599 99

Blockade of angiotensin II type 1 receptor (AT1) signaling attenuates heart failure following myocardial infarction (MI), perhaps through reduction of fibrosis in the noninfarcted myocardium. However, its specific effect on the infarct tissue itself has not been fully clarified, which we examined in the present study. After MI induction in mice, treatment with the AT1 blocker olmesartan, beginning on the 3rd day post-MI, significantly improved survival (94%) 4 wk post-MI, compared with saline (53%) and hydralazine (73%). Olmesartan-treated mice also showed significant attenuation of left ventricular dilatation and dysfunction, as well as significantly greater infarct wall thickness, although the absolute size of the infarct scar was unchanged. In addition, significantly greater numbers of nonmyocytes (mainly vascular cells and myofibroblasts) were present within the infarct scar in olmesartan-treated hearts. Ten days post-MI, apoptosis among granulation tissue cells was significantly suppressed in the olmesartan-treated hearts, where expression of Fas, Bax, procaspase-3, and Daxx and activation of caspase-3, c-Jun NH(2)-terminal kinase, and c-Jun were all significantly attenuated. By contrast, expression of Fas ligand, Bcl-2, and Fas-associated death domain and activation of caspase-8 were unaffected, suggesting olmesartan exerts a negative regulatory effect on the alternate pathway downstream of Fas receptor. In vitro, olmesartan dose-dependently inhibited Fas-mediated apoptosis in granulation tissue-derived myofibroblasts. The present study proposes this antiapoptotic effect as another important mechanism for an AT1 blocker in improving post-MI ventricular remodeling, as well as its antifibrotic effect, and also suggests a significant link between renin-angiotensin and Fas/Fas ligand systems in postinfarction hearts.
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PMID:Inhibition of Fas-associated apoptosis in granulation tissue cells accompanies attenuation of postinfarction left ventricular remodeling by olmesartan. 1720 88

Daxx is essential for embryonic development and implicated in apoptosis and transcriptional regulation. It is found only in the animal kingdom and appears to arise first in insects. In the Drosophila genus, the Daxx orthologs are much larger than those in other species. Here we show that in addition to a conserved core of approximately 200 residues, Daxx possesses several conserved domains and two essentially invariable short SUMO-interacting motifs (SIMs), each located at one or the other terminus of the protein. Both can independently interact with SUMO. The Daxx I7/733K double mutant with one mutation in each of the two SIMs no longer interacts with SUMO. Daxx interacts with Ubc9 and this interaction strictly requires at least one SIM. Interestingly, the Ubc9 H20D mutation that abolishes non-covalent Ubc9-SUMO interaction also interrupts Daxx-Ubc9 interaction. Thus, SUMO serves as the intermediate for Daxx-Ubc9 interaction. Surprisingly, Daxx I7/733K double mutant could still colocalize with PML. Furthermore, wt Daxx also strongly colocalizes with PMLDeltaS mutant, in which all three sumoylation sites are mutated, whereas PMLDeltaS only weakly colocalizes with Daxx I7/733K mutant, suggesting that SIM-SUMO interaction is not essential for but enhances PML-Daxx interaction. Remarkably, Daxx strongly stimulates c-Jun-mediated transcription and both SIMs are required for this stimulation. PML also activates c-Jun, which requires all three sumoylation sites. Coexpression of Daxx and PML revealed that they independently regulate c-Jun, with Daxx exerting a dominant role. These results suggest that the conserved SIMs are involved in mediating protein-protein interactions that underlie Daxx's diverse cellular functions.
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PMID:Identification of two independent SUMO-interacting motifs in Daxx: evolutionary conservation from Drosophila to humans and their biochemical functions. 1910 12


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