Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous study showed that mice lacking modulator recognition factor-2 (Mrf-2) were lean, with significant decreases in white adipose tissue. One postulated mechanism for the lean phenotype in Mrf-2 knockout mice is a defect in adipogenesis. In order to investigate this further, we examined the effects of Mrf-2 deficiency on adipogenesis in vitro. In mouse fibroblasts (MEFs) derived from Mrf-2(-/-) embryos, and in 3T3-L1 cells after knockdown of Mrf-2 by small interference RNA (siRNA) there was a potent inhibition of hormone-induced lipid accumulation, and significant decreases in the expression of the adipogenic transcription factors CCAAT/enhancer-binding protein (C/EBP) alpha and peroxisome proliferator-activated receptor-gamma and the mature adipocyte genes they control. Transduction of Mrf-2(-/-) MEFs with a retroviral vector expressing the longer Mrf-2 splice variant (Mrf-2B) stimulated both gene expression and lipid accumulation. Because 3T3-L1 cells are committed to the adipocyte lineage, we used this simpler model system to examine the effects of Mrf-2 deficiency on adipocyte maturation. Analyses of both mRNA and protein revealed that knockdown of Mrf-2 in 3T3-L1 cells prolonged the expression of C/EBP homologous protein-10, a dominant-negative form of C/EBP. Consistent with these findings, suppression of Mrf-2 also inhibited the DNA-binding activity of C/EBPbeta. These data suggest that Mrf-2 facilitates the induction of the two key adipogenic transcription factors C/EBPalpha and peroxisome proliferator-activated receptor-gamma indirectly by permitting hormone-mediated repression of the adipogenic repressor C/EBP homologous protein-10.
Mol Endocrinol 2008 Feb
PMID:Modulator recognition factor-2 is required for adipogenesis in mouse embryo fibroblasts and 3T3-L1 cells. 1796 84

In tumor cells growing under hypoxia, inhibiting glycolysis with 2-deoxy-d-glucose (2-DG) leads to cell death, whereas under normoxic conditions cells similarly treated survive. Surprisingly, here we find that 2-DG is toxic in select tumor cell lines growing under normal oxygen tension. In contrast, a more potent glycolytic inhibitor, 2-fluorodeoxy-d-glucose, shows little or no toxicity in these cell types, indicating that a mechanism other than inhibition of glycolysis is responsible for their sensitivity to 2-DG under normoxia. A clue to this other mechanism comes from previous studies in which it was shown that 2-DG interferes with viral N-linked glycosylation and is reversible by exogenous addition of mannose. Similarly, we find that 2-DG interferes with N-linked glycosylation more potently in the tumor cell types that are sensitive to 2-DG under normoxia, which can be reversed by exogenous mannose. Additionally, 2-DG induces an unfolded protein response, including up-regulation of GADD153 (C/EBP-homologous protein), an unfolded protein response-specific mediator of apoptosis, more effectively in 2-DG-sensitive cells. We conclude that 2-DG seems to be toxic in select tumor cell types growing under normoxia by inhibition of N-linked glycosylation and not by glycolysis. Because in a phase I study 2-DG is used in combination with an anticancer agent to target hypoxic cells, our results raise the possibility that in certain cases, 2-DG could be used as a single agent to selectively kill both the aerobic (via interference with glycosylation) and hypoxic (via inhibition of glycolysis) cells of a solid tumor.
Mol Cancer Ther 2007 Nov
PMID:Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation. 1802 88

This study examined how the neurotrophin, nerve growth factor (NGF), protects PC12 cells against endoplasmic reticulum (ER) stress-induced apoptosis. ER stress was induced using thapsigargin (TG) that inhibits the sarcoplasmic/ER Ca2+-ATPase pump (SERCA) and depletes ER Ca2+ stores. NGF pre-treatment inhibited translocation of Bax to the mitochondria, loss of mitochondrial transmembrane potential, cytochrome c release, activation of caspases (-3, -7 and -9) and apoptosis induction by TG. Notably, TG also caused a marked induction of BimEL mRNA and protein, and knockdown of Bim with siRNA protected cells against TG-induced apoptosis. NGF delayed the induction and increased the phosphorylation of BimEL. NGF-mediated protection was dependent on phosphatidylinositol-3 kinase (PI3K) signalling since all above apoptotic events, including expression and phosphorylation status of BimEL protein, could be reverted by the PI3K inhibitor LY294002. In contrast, NGF had no effect on the TG-mediated induction of the unfolded protein response (increased expression of Grp78, GADD34, splicing of XBP1 mRNA) or ER stress-associated pro-apoptotic responses (induction of C/EBP homologous protein [CHOP], induction and processing of caspase-12). These data indicate that NGF-mediated protection against ER stress-induced apoptosis occurs at the level of the mitochondria by regulating induction and activation of Bim and mitochondrial translocation of Bax.
J Cell Mol Med 2008 Dec
PMID:Nerve growth factor blocks thapsigargin-induced apoptosis at the level of the mitochondrion via regulation of Bim. 1826 51

Intrinsically disordered proteins are emerging as substantial functional constituents of mammalian proteomes. Although the abundance of these proteins has been established by bioinformatics approaches, the vast majority have not been characterized structurally or functionally. The C/EBP homologous protein (CHOP) is a proto-oncogene, traditionally shown as a dominant-negative inhibitor of C/EBPs and a transcriptional activator of activating protein-1. We report here the in vitro characterization of CHOP, where our computational analyses and experimental evidences show for the first time that CHOP is an intrinsically disordered protein. Intrinsic fluorescence, NMR spectroscopy, and analytical size-exclusion chromatography studies indicate that CHOP contains extensive disordered regions and self-associate in solution. Interestingly, the disordered N-terminal region has a key role in the oligomerization of CHOP and is vital for its biological activity. We report a novel mechanistic role of CHOP in the inhibition of Wnt/TCF signaling and stimulation of c-Jun and sucrase-isomaltase reporter activity in intestinal colon cancer cells. These findings are discussed in the context of oligomerization of intrinsically disordered proteins as one of the mechanisms through which they exert their biological function.
J Mol Biol 2008 Jul 04
PMID:Intrinsically disordered human C/EBP homologous protein regulates biological activity of colon cancer cells during calcium stress. 1853 16

Prolonged hyperglycaemia leads to impaired glucose-stimulated insulin secretion (GSIS) and apoptosis in insulin-producing beta-cells. The detrimental effects have been connected with glucose-induced lipid accumulation in the beta-cell. AMP-activated protein kinase (AMPK) agonist, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), promotes utilization of nutrient stores for energy production. It was tested how impaired GSIS and elevated apoptosis observed in insulinoma (INS)-1E cells after prolonged culture at 27 mM glucose were affected by the inclusion of 0.3 or 1 mM AICAR during culture. Glucose-induced impairment of insulin release was reverted by the inclusion of 0.3 but not 1 mM AICAR, which did not affect insulin content. The glucose-induced rise in triglyceride (TG) content observed in the cells cultured at 27 mM glucose was not altered by the inclusion of either 0.3 or 1 mM AICAR. Inclusion of 1 but not 0.3 mM AICAR during culture induced phosphorylation of AMPK and its downstream target acyl-CoA carboxylase. Phosphorylation was paralleled by reduced number of apoptotic cells and lowered expression of pro-apoptotic C/EBP homologous protein (CHOP). In conclusion, AICAR dose dependently improves beta-cell function and reduces apoptosis in beta-cells exposed to prolonged hyperglycaemia without changing TG levels.
J Mol Endocrinol 2008 Sep
PMID:AMP-activated protein kinase agonist dose dependently improves function and reduces apoptosis in glucotoxic beta-cells without changing triglyceride levels. 1857 84

Brefeldin A induces apoptosis in PC-3 and MCF-7 cells at a concentration of 30 ng/ml. RT-PCR analyses showed up-regulation of CHOP/GADD153 and splicing of XBP-1 mRNA in brefeldin A-treated cells. CHOP promoter-luciferase reporter assays demonstrated activation of AARE, ERSE, and AP-1 elements of CHOP promoter by brefeldin A treatment. The activation of these elements was not affected by preincubation of cells with N-acetyl-cysteine (NAC), L: -buthionine-(S,R)-sulfoximine (BSO), and c-Jun N-terminal kinase (JNK) inhibitor (SP600125), suggesting that activation of CHOP promoter by brefeldin A may not involve oxidative stress or JNK signaling pathway. On the other hand, brefeldin A-induced apoptosis was not affected by NAC and BSO pretreatment, but was completely suppressed by JNK inhibitor pretreatment. Our results suggest that although CHOP is up-regulated by brefeldin A, it is not a major mediator of brefeldin A-induced apoptosis.
Mol Cell Biochem 2008 Dec
PMID:Brefeldin A activates CHOP promoter at the AARE, ERSE and AP-1 elements. 1867 84

Previous studies have implicated the unfolded protein response (UPR) in the pathogenesis of Alzheimer's disease (AD). We previously reported that DNA variants in the ubiquilin 1 (UBQLN1) gene increase the risk for AD. Since UBQLN1 has been shown to play a role in the UPR, we assessed the effects of overexpression and downregulation of UBQLN1 splice variants during tunicamycin-induced ER stress. In addition to previously described transcript variants, TV1 and TV2, we identified two novel transcript variants of UBQLN1 in brain: TV3 (lacking exons 2-4) and TV4 (lacking exon 4). Overexpression of TV1-3, but not TV4 significantly decreased the mRNA induction of UPR-inducible genes, C/EBP homologous protein (CHOP), BiP/GRP78, and protein disulfide isomerase (PDI) during the UPR. Stable overexpression of TV1-3, but not TV4, also significantly decreased the induction of CHOP protein and increased cell viability during the UPR. In contrast, downregulation of UBQLN1 did not affect CHOP mRNA induction, but instead increased PDI mRNA levels. These findings suggest that overexpression UBQLN1 transcript variants TV1-3, but not TV4, exert a protective effect during the UPR by attenuating CHOP induction and potentially increasing cell viability.
J Mol Neurosci 2009 May
PMID:Effects of ubiquilin 1 on the unfolded protein response. 1895 72

Cellular stresses such as disruption of calcium homeostasis, inhibition of protein glycosylation, and reduction of disulfide bonds result in accumulation of misfolded proteins in the endoplasmic reticulum (ER) and lead to cell death by apoptosis. Tunicamycin, which is an inhibitor of protein glycosylation, induces ER stress and apoptosis. In this study, we examined the involvement of double-stranded RNA (dsRNA)-activated protein kinase (PKR) and its protein activator PACT in tunicamycin-induced apoptosis. We demonstrate for the first time that PACT is phosphorylated in response to tunicamycin and is responsible for PKR activation by direct interaction. Furthermore, PACT-induced PKR activation is essential for tunicamycin-induced apoptosis, since PACT as well as PKR null cells are markedly resistant to tunicamycin and show defective eIF2alpha phosphorylation and C/EBP homologous protein (CHOP, also known as GADD153) induction especially at low concentrations of tunicamycin. Reconstitution of PKR and PACT expression in the null cells renders them sensitive to tunicamycin, thus demonstrating that PACT-induced PKR activation plays an essential function in induction of apoptosis.
J Mol Biol 2009 Jan 16
PMID:Essential role of PACT-mediated PKR activation in tunicamycin-induced apoptosis. 1900 93

Sarcolemmal Na(+)/H(+) exchanger (NHE) activity, which is provided by the NHE isoform 1 (NHE1), has been implicated in ischemia/reperfusion-induced myocardial injury in animal models and humans, on the basis of studies with pharmacological NHE1 inhibitors. We generated a transgenic (TG) mouse model with cardiac-specific over-expression of NHE1 to determine whether this would be sufficient to increase myocardial susceptibility to ischemia/reperfusion-induced injury. TG mouse hearts exhibited increased sarcolemmal NHE activity and normal morphology and function. Surprisingly, they also showed reduced susceptibility to ischemia/reperfusion-induced injury, as reflected by improved functional recovery and smaller infarcts. Such protection was sustained in the presence of NHE1 inhibition with zoniporide, indicating a mechanism that is independent of sarcolemmal NHE activity. Immunoblot analysis revealed accumulation of immature NHE1 protein as well as marked upregulation of both cytoprotective (78/94 kDa glucose-regulated proteins, calreticulin, protein disulfide isomerase) and pro-apoptotic (C/EBP homologous protein) components of the endoplasmic reticulum (ER) stress response in TG myocardium. With increasing age, NHE1 TG mice exhibited increased myocyte apoptosis, developed left ventricular contractile dysfunction, underwent cardiac remodelling and died prematurely. Our findings indicate that: (1) Cardiac-specific NHE1 over-expression induces the ER stress response in mouse myocardium, which may afford protection against ischemia/reperfusion-induced injury despite increased NHE activity; (2) Ageing NHE1 TG mice exhibit myocyte apoptosis, cardiac remodelling and failure, likely as a result of sustained ER stress; (3) The pluripotent effects of the ER stress response may confound studies that are based on the chronic over-expression of complex proteins in myocardium.
J Mol Cell Cardiol 2009 Feb
PMID:Paradoxical resistance to myocardial ischemia and age-related cardiomyopathy in NHE1 transgenic mice: a role for ER stress? 1902 22

Fatty acid synthase (FASN) is the terminal enzyme responsible for fatty acid synthesis and is up-regulated in tumors of various origins to facilitate their growth and progression. Because of several reports linking the FASN and proteasome pathways, we asked whether FASN inhibitors could combine with bortezomib, the Food and Drug Administration-approved proteasome inhibitor, to amplify cell death. Indeed, bortezomib treatment augmented suboptimal FASN inhibitor concentrations to reduce clonogenic survival, which was paralleled by an increase in apoptotic markers. Interestingly, FASN inhibitors induced accumulation of ubiquinated proteins and enhanced the effects of bortezomib treatment. In turn, bortezomib increased fatty acid synthesis, suggesting crosstalk between the pathways. We hypothesized that cell death resulting from crosstalk perturbation was mediated by increased unfolded protein response (UPR) signaling. Indeed, disruption of crosstalk activated and saturated the adaptation arm of UPR signaling, including eIF2alpha phosphorylation, activating transcription factor 4 expression, and X-box-binding protein 1 splicing. Furthermore, although single agents did not activate the alarm phase of the UPR, crosstalk interruption resulted in activated c-Jun NH2-terminal kinase and C/EBP homologous protein-dependent cell death. Combined, the data support the concept that the UPR balance between adaptive to stress signaling can be exploited to mediate increased cell death and suggests novel applications of FASN inhibitors for clinical use.
Mol Cancer Ther 2008 Dec
PMID:Disruption of crosstalk between the fatty acid synthesis and proteasome pathways enhances unfolded protein response signaling and cell death. 1907 56


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