Showing papers on "Transcription Factor CHOP published in 2002"
TL;DR: It is concluded that ER overload in beta cells causes ER stress and leads to apoptosis via Chop induction and a new therapeutic approach for preventing the onset of diabetes by inhibiting Chop induction or by increasing chaperone capacity in the ER is suggested.
Abstract: Overload of pancreatic β cells in conditions such as hyperglycemia, obesity, and long-term treatment with sulfonylureas leads to β cell exhaustion and type 2 diabetes. Because β cell mass declines under these conditions, apparently as a result of apoptosis, we speculated that overload kills β cells as a result of endoplasmic reticulum (ER) stress. The Akita mouse, which carries a conformation-altering missense mutation (Cys96Tyr) in Insulin 2, likewise exhibits hyperglycemia and a reduced β cell mass. In the development of diabetes in Akita mice, mRNAs for the ER chaperone Bip and the ER stress–associated apoptosis factor Chop were induced in the pancreas. Overexpression of the mutant insulin in mouse MIN6 β cells induced Chop expression and led to apoptosis. Targeted disruption of the Chop gene delayed the onset of diabetes in heterozygous Akita mice by 8–10 weeks. We conclude that ER overload in β cells causes ER stress and leads to apoptosis via Chop induction. Our findings suggest a new therapeutic approach for preventing the onset of diabetes by inhibiting Chop induction or by increasing chaperone capacity in the ER.
904 citations
TL;DR: The discovery and characterization of a mitochondrial stress response in mammalian cells is reported on and it is found that the accumulation of unfolded protein within the mitochondrial matrix results in the transcriptional upregulation of nuclear genes encoding mitochondrial stress proteins, but not those encoding stress proteins of the endoplasmic reticulum.
Abstract: Cells respond to a wide variety of stresses through the transcriptional activation of genes that harbour stress elements within their promoters. While many of these elements are shared by genes encoding proteins representative of all subcellular compartments, cells can also respond to stresses that are specific to individual organelles, such as the endoplasmic reticulum un folded protein response. Here we report on the discovery and characterization of a mitochondrial stress response in mammalian cells. We find that the accumulation of unfolded protein within the mitochondrial matrix results in the transcriptional upregulation of nuclear genes encoding mitochondrial stress proteins such as chaperonin 60, chaperonin 10, mtDnaJ and ClpP, but not those encoding stress proteins of the endoplasmic reticulum. Analysis of the chaperonin 60/10 bidirectional promoter identified a CHOP element as the mitochondrial stress response element. Dominant-negative mutant forms of CHOP and overexpression of CHOP revealed that this transcription factor, in association with C/EBPβ, regulates expression of mitochondrial stress genes in response to the accumulation of unfolded proteins.
844 citations
TL;DR: The data indicate that both the ERSE and the PERK-ATF4 pathways converge on the CHOP promoter during ER stress and provide insights into the similarities and differences between CHOP and ER chaperone expression during normal and stress conditions.
670 citations
TL;DR: It is found that the stress of unfolded proteins in the endoplasmic reticulum (ER) activates P58IPK gene transcription through an ER stress-response element in its promoter region and plays a functional role in the expression of downstream markers of PERK activity in the later phase of the ER-stress response.
Abstract: P58IPK is an Hsp40 family member known to inhibit the interferon (IFN)-induced, double-stranded RNA-activated, eukaryotic initiation factor 2α (eIF2α) protein kinase R (PKR) by binding to its kinase domain. We find that the stress of unfolded proteins in the endoplasmic reticulum (ER) activates P58IPK gene transcription through an ER stress-response element in its promoter region. P58IPK interacts with and inhibits the PKR-like ER-localized eIF2α kinase PERK, which is normally activated during the ER-stress response to protect cells from ER stress by attenuating protein synthesis and reducing ER client protein load. Levels of phosphorylated eIF2α were lower in ER-stressed P58IPK-overexpressing cells and were enhanced in P58IPK mutant cells. In the ER-stress response, PKR-like ER kinase (PERK)-mediated translational repression is transient and is followed by translational recovery and enhanced expression of genes that increase the capacity of the ER to process client proteins. The absence of P58IPK resulted in increased expression levels of two ER stress-inducible genes, BiP and Chop, consistent with the enhanced eIF2α phosphorylation in the P58IPK deletion cells. Our studies suggest that P58IPK induction during the ER-stress response represses PERK activity and plays a functional role in the expression of downstream markers of PERK activity in the later phase of the ER-stress response.
387 citations
TL;DR: It is demonstrated that as evidenced by certain chaperone inductions, Jev infection triggers the UPR in fibroblast BHK-21 cells and in neuronal N18 and NT-2 cells, in which JEV results in apoptotic cell death, suggesting that virus-induced ER stress may participate, via p38-dependent and CHOP-mediated pathways, in the apoptotic process triggered by JEV infection.
Abstract: The malfunctioning of the endoplasmic reticulum (ER) of cells in hosts ranging from yeast to mammals can trigger an unfolded protein response (UPR). Such malfunctioning can result from a variety of ER stresses, including the inhibition of protein glycosylation and calcium imbalance. To cope with ER stresses, cells may rely on the UPR to send a signal(s) from the ER to the nucleus to stimulate appropriate cellular responses, including induction of chaperone expression. During Japanese encephalitis virus (JEV) infection, the lumen of the ER rapidly accumulates substantial amounts of viral proteins for virus progeny production. In the present study, we demonstrate that as evidenced by certain chaperone inductions, JEV infection triggers the UPR in fibroblast BHK-21 cells and in neuronal N18 and NT-2 cells, in which JEV results in apoptotic cell death. By contrast, no UPR was observed in apoptosis-resistant K562 cells infected by JEV. JEV infection also activates expression of CHOP/GADD153, a distinctive transcription factor often induced by the UPR, and appears to trigger activation of p38 mitogen-activated protein kinase, a posttranslational activator of CHOP. Ectopic enforcement of CHOP expression enhanced JEV-induced apoptosis, whereas treatment with a p38-specific inhibitor, SB203580, partially blocked JEV-induced apoptosis. Interestingly, bcl-2 overexpression and treatment with a pancaspase inhibitor, z-VAD-fmk, inhibited CHOP induction and diminished JEV-induced apoptosis, suggesting that Bcl-2 and caspases could be the upstream regulators of CHOP. Our results thus suggest that virus-induced ER stress may participate, via p38-dependent and CHOP-mediated pathways, in the apoptotic process triggered by JEV infection.
315 citations
TL;DR: It is shown that major UPR components are activated in B cells stimulated to secrete antibody, suggesting that a physiological UPR elicited during differentiation of B-lymphocytes into high-rate secretory cells may be distinct from the UPR defined by agents that disrupt protein maturation in the ER.
296 citations
TL;DR: PMD represents the first member of a novel class of disparate degenerative diseases for which UPR activation and signaling is the common pathogenic mechanism and has the potential to modulate disease severity in many cells expressing mutant secretory pathway proteins.
261 citations
TL;DR: It is found that C/EBPβ induces neuronal differentiation and that this process is inhibited by transfection with the C/ EBP homologous protein 10 (CHOP), strongly suggesting that the extension of neurites is indeed due to the C-EBP β transcriptional activity.
87 citations
TL;DR: There are significant differences in the molecular mechanisms involved in the transcriptional activation of CHOP and AS by amino acid limitation, according to the AStranscriptional control elements used by the amino acid pathway.
86 citations
TL;DR: The ability of flavonoids to regulate MAPK-responsive pathways in a selective manner indicates a mechanism by which phytochemicals may influence human health and disease.
Abstract: Phytochemicals bind to and regulate the human estrogen receptors (ERalpha and ERbeta), mimicking actions of the endogenous estrogen, 17beta-estradiol, and known antiestrogens such as ICI 182,780. Recently, however, some of these estrogenic phytochemicals have been shown to affect other signal transduction pathways, such as receptor tyrosine kinases and mitogen-activated protein kinases (MAPK). Previously, we found that certain phytochemicals, such as flavone, apigenin, kaempferide and chalcone, have potent antiestrogenic activity. However, the antiestrogenicity of these compounds does not correlate with their ER binding capacity, suggesting alternative signaling as a mechanism for their antagonistic effects. In this study, we examined the effects of these compounds on the transcription factor activator protein-1 (AP-1). Using AP-1-luciferase stable human endometrial adenocarcinoma Ishikawa and human embryonic kidney (HEK) 293 cells, chalcone, flavone and apigenin all stimulated AP-1 activity. Additionally, we determined the effects of the phytochemicals on transcription factors that are downstream targets of various MAPK pathways. To test this, we used HEK 293 cells stably cointegrated with GAL4 transcriptional activation systems of Elk-1, c-Jun or C/EBP homologous protein (CHOP). Chalcone was the only phytochemical that activated all three transcription factors [Elk-1, 2.7-fold (P < 0.001); c-Jun, 2.7-fold (P = 0.025); CHOP, 3.0-fold (P = 0.002)], whereas apigenin stimulated CHOP (3.9-fold; P < 0.001), but inhibited phorbol myristoyl acetate-induced c-Jun activity (71%;P = 0.006). This work suggests that phytochemicals affect multiple signaling pathways that converge at the level of transcriptional regulation. The ability of flavonoids to regulate MAPK-responsive pathways in a selective manner indicates a mechanism by which phytochemicals may influence human health and disease.
74 citations
TL;DR: It is demonstrated that in human myxoid liposarcoma cells, wild‐type TLS binds to RNA polymerase II (Pol II) via its N‐terminal domain and to the transcription and translation factor Y‐box binding protein‐1 (YB‐1) through its C‐terminals, suggesting that aberrant RNA splicing may be a common feature of human sarcomas.
TL;DR: It is reported that recombinant TLS‐CHOP‐green fluorescence protein localizes to nuclear structures, similar to, but distinct from, PML nuclear bodies.
Abstract: CHOP in 12q13, also called GADD153 or DDIT3, encodes a transcription factor of the C/EBP type. As a result of t(12;16) translocations, CHOP is rearranged and fused to TLS in 16p11 in about 90% of myxoid liposarcomas/round cell liposarcomas (MLS/RCLS). The TLS-CHOP protein consists of the N-terminal half of TLS juxtaposed to the N-terminal of the entire CHOP. It is capable of forming dimers with the natural dimer partners of CHOP. Here we report that recombinant TLS-CHOP-green fluorescence protein localizes to nuclear structures, similar to, but distinct from, PML nuclear bodies. The TLS-CHOP-green fluorescent protein nuclear structures are resistant to high salt concentration and nuclease treatment. Transfection of TLS-CHOP to normal fibroblasts causes a rapid down regulation and relocation of PML nuclear bodies. An abnormal extra nuclear localization of PML bodies was also found in TLS-CHOP carrying cell lines established from myxoid liposarcomas. Transfection of TLS-CHOP induced a rapid disappearance of PCNA. TLS-CHOP may disturb the nuclear machinery by binding and sequestering important factors from their natural sites.
TL;DR: In this article, the authors investigated the role of the SYGQ-rich TLS N-terminal in the localization of TLS-CHOP to nuclear structures, and reported the temperature-dependent localization and association with Cajal bodies.