Showing papers on "Transcription Factor CHOP published in 2005"
TL;DR: The results indicate that TRB3 is a novel target of CHOP/ATF4 and downregulates its own induction by repression of CHop/atF4 functions, and that it is involved in CHOP‐dependent cell death during ER stress.
Abstract: C/EBP homologous protein (CHOP) is a stress-inducible nuclear protein that is crucial for the development of programmed cell death and regeneration; however, the regulation of its function has not been well characterized. Slbo, a Drosophila homolog of C/EBP (CCAAT/enhancer binding protein), was shown to be unstabilized by tribbles. Here, we identified TRB3 as a tribbles ortholog in humans, which associated with CHOP to suppress the CHOP-dependent transactivation. TRB3 is induced by various forms endoplasmic reticulum (ER) stress later than CHOP. Tunicamycin treatment enhanced the TRB3 promoter activity, while dominant-negative forms of CHOP suppressed the tunicamycin-induced activation. In addition, the tunicamycin response region in the TRB3 promoter contains amino-acid response elements overlapping the CHOP-binding site, and CHOP and ATF4 cooperated to activate this promoter activity. Knockdown of endogenous ATF4 or CHOP expression dramatically repressed tunicamycin-induced TRB3 induction. Furthermore, knockdown of TRB3 expression decreased ER stress-dependent cell death. These results indicate that TRB3 is a novel target of CHOP/ATF4 and downregulates its own induction by repression of CHOP/ATF4 functions, and that it is involved in CHOP-dependent cell death during ER stress.
878 citations
TL;DR: The role of CHOP depends on the nature of the toxic stimulus, and for 6OHDA, an oxidative metabolite of dopamine, it is a mediator of apoptotic death.
Abstract: There is increasing evidence that neuron death in neurodegenerative diseases, such as Parkinson's disease, is due to the activation of programmed cell death. However, the upstream mediators of cell death remain largely unknown. One approach to the identification of upstream mediators is to perform gene expression analysis in disease models. Such analyses, performed in tissue culture models induced by neurotoxins, have identified up-regulation of CHOP/GADD153, a transcription factor implicated in apoptosis due to endoplasmic reticulum stress or oxidative injury. To evaluate the disease-related significance of these findings, we have examined the expression of CHOP/GADD153 in neurotoxin models of parkinsonism in living animals. Nuclear expression of CHOP protein is observed in developmental and adult models of dopamine neuron death induced by intrastriatal injection of 6-hydroxydopamine (6OHDA) and in models induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). CHOP is a mediator of neuron death in the adult 60HDA model because a null mutation results in a reduction in apoptosis. In the chronic MPTP model, however, while CHOP is robustly expressed, the null mutation does not protect from the loss of neurons. We conclude that the role of CHOP depends on the nature of the toxic stimulus. For 6OHDA, an oxidative metabolite of dopamine, it is a mediator of apoptotic death.
287 citations
TL;DR: It is concluded that eIF2α kinases are integral to cellular stress pathways induced by proteasome inhibitors, and may be central to the efficacy of anticancer drugs that target the ubiquitin/proteasome pathway.
285 citations
TL;DR: It is suggested that specific ER stress signaling transmitted by ATF6 leads to naturally occurring apoptosis during muscle development, as well as other ER stress sensors activated during apoptosis in myoblasts.
Abstract: Although apoptosis occurs during myogenesis, its mechanism of initiation remains unknown. In a culture model, we demonstrate activation of caspase-12, the initiator of the endoplasmic reticulum (ER) stress-specific caspase cascade, during apoptosis associated with myoblast differentiation. Induction of ER stress-responsive proteins (BiP and CHOP) was also observed in both apoptotic and differentiating cells. ATF6, but not other ER stress sensors, was specifically activated during apoptosis in myoblasts, suggesting that partial but selective activation of ER stress signaling was sufficient for induction of apoptosis. Activation of caspase-12 was also detected in developing muscle of mouse embryos and gradually disappeared later. CHOP was also transiently induced. These results suggest that specific ER stress signaling transmitted by ATF6 leads to naturally occurring apoptosis during muscle development.
201 citations
TL;DR: It is reported that CCAAT/enhancer-binding protein homologous protein (CHOP) is a regulator of DR5 induction by proteasome inhibitor MG132, and results indicate that the proteasomesome inhibitors MG132 induces DR5 expression through CHOP up-regulation.
Abstract: Combined treatment with a proteasome inhibitor and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising strategy for cancer therapy. Proteasome inhibitors induce the expression of death receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechanism of DR5 up-regulation has not been elucidated. In this study, we report that CCAAT/enhancer-binding protein homologous protein (CHOP) is a regulator of DR5 induction by proteasome inhibitor MG132. MG132 induced DR5 expression at a protein and mRNA level in prostate cancer DU145 cells. Furthermore, MG132 increased DR5 promoter activity. Using a series of deletion mutant plasmids containing DR5 promoters of various sizes, we found that MG132 stimulated the promoter activity via the region of -289 to -253. This region contained a CHOP-binding site. Site-directed mutation of the site abrogated the promoter activity enhanced by MG132. An electrophoretic mobility shift assay showed that CHOP directly bound to the MG132-responsive site on the DR5 promoter. Expression of the CHOP protein was increased with MG132 along with DR5 up-regulation. Furthermore, CHOP small interfering RNA attenuated the DR5 up-regulation due to MG132. These results indicate that the proteasome inhibitor MG132 induces DR5 expression through CHOP up-regulation.
173 citations
TL;DR: Microarray studies confirmed by PCR analysis and western blotting indicate that genes affected by CHOP are both proapoptotic and antiapoptosis and CHOP induction by ethanol may tip the balance of cell survival and death toward apoptosis.
Abstract: Background: CHOP is a transcriptional regulator involved in apoptosis caused by endoplasmic reticulum (ER) stress. We previously reported that CHOP as well as other ER stress response genes is induced in the liver of a murine model of intragastric ethanol feeding. This study was undertaken to determine the role of CHOP in hepatocellular apoptosis and liver injury in this model.
Methods: CHOP wild-type (+/+) mice and CHOP null (-/-) mice were fed alcohol for four weeks with glucose as control. Hematoxylin-eosin staining, TUNEL, and caspase 3 staining of liver tissues were performed for assessment of fatty liver, necroinflammation, and apoptosis. Total RNA was extracted for microarray and reverse transcription-PCR analyses, and proteins were used for western blotting.
Results: Significant increased liver/body ratio, steatosis, liver triglyceride levels, and plasma homocysteine concentrations were observed in alcohol-fed mice as compared with controls in both genotypes. There was no significant difference between wild-type and CHOP null (-/-) mice in the parameters related to fatty liver. Alcohol-induced increased serum alanine aminotransferase levels and necroinflammatory foci were not significantly reduced in CHOP null (-/-) mice. However, apoptosis was present in alcohol-fed wild-type mice but virtually absent in alcohol-fed CHOP null (-/-) mice. The ER stress response indicated by increased Grp78 mRNA was observed in both types of mice fed alcohol. Of 12,423 transcripts analyzed for ≥ two-fold changes, several related to apoptosis were influenced by CHOP: Gadd45 and cathepsin B were up-regulated in ethanol-fed wild-type mice but not in CHOP null (-/-) mice, whereas Jun D and Bcl-xL were down-regulated in ethanol-fed wild-type mice but not in ethanol-fed CHOP null (-/-) mice.
Conclusions: CHOP null (-/-) mice have remarkable absence of hepatocellular apoptosis in response to alcohol feeding but no protection against hyperhomocysteinemia, ER stress, and fatty liver. Thus, CHOP up-regulation occurs downstream of and contributes to one manifestation of ER stress, namely, apoptosis. Microarray studies confirmed by PCR analysis and western blotting indicate that genes affected by CHOP are both proapoptotic and antiapoptotic and CHOP induction by ethanol may tip the balance of cell survival and death toward apoptosis.
155 citations
TL;DR: Ca2+-stimulated calpain activity and CHOP expression play important roles in celecoxib-induced apoptosis in gastric mucosal cells, and data indicate that the increase in intracellular Ca2+ levels that is observed in the presence of NSAIDs is due to the stimulation of Ca 2+ influx across the cytoplasmic membrane, which results from their membrane permeabilization activity.
110 citations
TL;DR: Overexpression of the C/EBP homologous transcription factor CHOP impaired transcriptional activation of the asparagine synthetase promoter following amino acid deprivation or over-expression of ATF5 or CREB2/ATF4 indicates that CHOP functions as a shut-off-device for nutrient deprivation-induced gene transcription.
Abstract: Asparagine synthetase catalyses the glutamine- and ATP-dependent conversion of aspartic acid to asparagine. In human hepatoma cells cultured in medium containing amino acids, the mRNA of asparagine synthetase is not detectable by RNase protection mapping. However, maintaining the cells in amino acid-free Krebs-Ringer bicarbonate buffer strongly upregulated asparagine synthetase biosynthesis. The effect of amino acid deprivation on asparagine synthetase gene transcription is mediated by a genetic element termed the nutrient-sensing response unit. Previous studies revealed that the basic region leucine zipper (bZIP) transcription factor CREB2/ATF4 is involved in the nutrient deprivation-induced upregulation of asparagine synthetase gene transcription. Here we show that overexpression of the bZIP protein ATF5, a transcriptional activator, stimulates asparagine synthetase promoter/reporter gene transcription via the nutrient-sensing response unit. In contrast, ATF5 does not transactivate cAMP response element (CRE)-containing reporter genes. Overexpression of the C/EBP homologous transcription factor CHOP impaired transcriptional activation of the asparagine synthetase promoter following amino acid deprivation or over-expression of ATF5 or CREB2/ATF4. These data indicate that CHOP functions as a shut-off-device for nutrient deprivation-induced gene transcription.
58 citations
TL;DR: These studies establish a system whereby a terminal or adaptive UPR can be alternatively triggered by physiologic stimuli, as well as identifying B cell receptor (BCR) signaling as an unexpected physiologic UPR trigger and demonstrating that in mature B cells, BCR stimulation induces a short lived UPR similar to the LPS-triggered nonclassical UPR.
56 citations
TL;DR: It is demonstrated that C/EBPbeta, whose activity is enhanced by a variety of cytokines during the course of viral infection, can stimulate basal- and Tat-mediated transcription of MCP-1 in human astrocytic cells and suggest that the delicate balance among the downstream regulatory proteins of several cytokines and immunomodulators can dictate the level of expression of chemoattractants.
52 citations
TL;DR: It is suggested that bromovulone III induces apoptosis in Hep3B cells through a mechanism that induces ER stress and leads to activation of CHOP/GADD153 and caspase-12.
TL;DR: It is shown that the transcription factor CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) directly interacts with GABAB receptors in a subtype-selective manner to regulate cell surface expression of GABAB1a/GABAB2 receptors upon co-expression in HEK 293 cells.
TL;DR: Overall, the data suggest that CHOP participates in adaptive responses of the epidermis following UVB/UVA exposure in vivo, thus implicating CHOP in sunburn cell (SBC) formation.
TL;DR: The novel findings that oncogenic Ras downregulates Gadd153 expression at both protein and mRNA levels are reported and that such downregulation occurs, at least in part, via decreases in GADD153 mRNA stability are reported.
Abstract: Oncogenic Ras proteins transform cells via multiple downstream signaling cascades that are important for cell proliferation and survival. Gadd153, also known as CHOP, is a growth inhibitory and proapoptotic protein and its expression is upregulated by many agents that induce apoptosis. Here, we report our novel findings that oncogenic Ras downregulates Gadd153 expression at both protein and mRNA levels and that such downregulation occurs, at least in part, via decreases in GADD153 mRNA stability. Gadd153 downregulation is specific to oncogenic Ras since another oncogenic family member R-Ras2/TC21 does not downregulate Gadd153. We further demonstrate that the expression of exogenous Gadd153 interferes with Ras-induced oncogenic transformation, which suggests that downregulation of Gadd153 appears to be an important mechanism by which oncogenic Ras promotes cellular transformation. Thus, oncogenic Ras-mediated cellular transformation also involves downmodulation of important molecules such as Gadd153 that negatively regulate cell growth and survival.