Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Levels of Rb2/p130 protein are increased 5-10-fold following all-trans-retinoic acid (ATRA) treatment of the retinoid-sensitive ovarian adenocarcinoma cell line CAOV3, but not the retinoid-resistant adenocarcinoma cell line SKOV3. We found that this increase in Rb2/p130 protein levels in ATRA-treated CAOV3 cells was the result of an increased protein stability. Moreover, Rb2/p130 exhibited a decreased ubiquitination following ATRA treatment. Because phosphorylation frequently mediates ubiquitination of proteins, we examined the serine/threonine phosphatase activity in our CAOV3 cells following ATRA treatment. A significant increase in Ser/Thr phosphatase activity was found, which correlated with a rise in the level of protein phosphatase 2A (PP2A) catalytic subunit-alpha. In addition, co-immunoprecipitation and glutathione S-transferase pull-down studies demonstrated that PP2A and Rb2/p130 associate. We have made use of a battery of Rb2/p130 mutants to determine the sites dephosphorylated in response to ATRA treatment of CAOV3 cells. Obligate CDK4 phosphorylation sites seemed most important to the stability of the protein and are among the candidate sites that are dephosphorylated by PP2A following ATRA treatment. Finally, using both small interfering RNA specific to the catalytic subunit of PP2A and a variant of the SKOV3 cell line that overexpresses PP2A, we have shown that modulation of PP2A protein levels correlates with the ability of ATRA to inhibit growth of ovarian carcinoma cells. Our data suggest that ATRA mediates growth inhibition by stabilizing Rb2/p130 via a mechanism that involves induction of PP2A, an enzyme that can potentially dephosphorylate Rb2/p130, thereby protecting it from degradation by the proteasome.
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PMID:Protein phosphatase 2A associates with Rb2/p130 and mediates retinoic acid-induced growth suppression of ovarian carcinoma cells. 1291 4

The abnormal expression of breast cancer-specific gene 1 (BCSG1) in malignant mammary epithelial cells is highly associated with the development and progression of breast cancer. A series of in vitro and in vivo studies performed in our laboratory and others have demonstrated that BCSG1 expression significantly stimulates proliferation, invasion, and metastasis of breast cancer cells. However, currently little is known about how BCSG1 exerts its oncogenic functions. To elucidate the cellular mechanisms underlying the effects of BCSG1 in breast cancer cells, we used a yeast two-hybrid system to screen for proteins that could associate with BCSG1. Through this screening, we identified the mitotic checkpoint protein BubR1 as a novel binding partner of BCSG1. The specific association of BCSG1 with BubR1 in breast cancer cells was demonstrated by immunoprecipitation and GST pull-down assays. Intriguingly, experiments conducted in four different cell lines all showed that exogenous expressions of BCSG1 consistently reduce the cellular levels of the BubR1 protein without affecting BubR1 mRNA expression. The tendency of endogenous BCSG1 expression coinciding with lower BubR1 protein levels was also observed in seven out of eight breast cancer cell lines. We further showed that the reducing effect of BCSG1 on BubR1 protein expression could be prevented by treating BCSG1-transfected cells with MG-132, a selective 26S proteasome inhibitor, implying that the proteasome machinery may be involved in the BCSG1-induced reduction of the BubR1 protein. Accompanied with a reduction of BubR1 protein level, BCSG1 expression resulted in multinucleation of breast cancer cells upon treatment with spindle inhibitor nocodazole, indicating an impaired mitotic checkpoint. Taken together, our novel findings suggest that BCSG1 may accelerate the progression of breast cancer at least in part by compromising the mitotic checkpoint control through inactivation of BubR1.
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PMID:Breast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1. 1457 21

Human Aurora/Ipl1-related kinase 2 (Aurora-B) is a key regulator of mitosis. Here human proteasome alpha-subunit C8 (HC8) was identified to interact with the Aurora-B by yeast two-hybrid screen. This finding was confirmed by GST pull-down assays and immunoprecipitation experiments. The Aurora-B protein level increased in HeLa cells cultured with proteasome inhibitor ALLN. Our data suggest that Aurora-B might undergo degradation by binding to HC8 in a proteasome-dependent manner during mitosis.
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PMID:Human aurora-B binds to a proteasome alpha-subunit HC8 and undergoes degradation in a proteasome-dependent manner. 1467 94

Bim, a "BH3-only" protein, is expressed de novo following withdrawal of serum survival factors and promotes cell death. We have shown previously that activation of the ERK1/2 pathway promotes phosphorylation of Bim(EL), targeting it for degradation via the proteasome. However, the nature of the kinase responsible for Bim(EL) phosphorylation remained unclear. We now show that Bim(EL) is phosphorylated on at least three sites in response to activation of the ERK1/2 pathway. By using the peptidylprolyl isomerase, Pin1, as a probe for proline-directed phosphorylation, we show that ERK1/2-dependent phosphorylation of Bim(EL) occurs at (S/T)P motifs. ERK1/2 phosphorylates Bim(EL), but not Bim(S) or Bim(L), in vitro, and mutation of Ser(65) to alanine blocks the phosphorylation of Bim(EL) by ERK1/2 in vitro and in vivo and prevents the degradation of the protein following activation of the ERK1/2 pathway. We also find that ERK1/2, but not JNK, can physically associate with GST-Bim(EL), but not GST-Bim(L) or GST-Bim(S), in vitro. ERK1/2 also binds to full-length Bim(EL) in vivo, and we have localized a potential ERK1/2 "docking domain" lying within a 27-amino acid stretch of the Bim(EL) protein. Our findings provide new insights into the post-translational regulation of Bim(EL) and the role of the ERK1/2 pathway in cell survival signaling.
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PMID:Extracellular signal-regulated kinases 1/2 are serum-stimulated "Bim(EL) kinases" that bind to the BH3-only protein Bim(EL) causing its phosphorylation and turnover. 1468 Dec 25

The apoptosis protection by plasminogen activator inhibitor -2(PAI-2) is dependent on a 33 amino acids fragment between helix C and D of PAI-2 which is probably may be due to the interaction of PAI-2 with unknown intracellular proteins. In this study we used the fragment between helix C and D of PAI-2 as bait to screen a HeLa cells cDNA library constructed during apoptosis in a yeast two-hybrid system and retrieved a clone that encodes 241 amino acids of proteasome (prosome, macropain) subunit, beta type 1(PSMbeta1) which plays important roles in NF-kappaB activation. GST-pulldown experiments confirmed the interaction between PAI-2 and PSMB1 in vitro. These data suggest that the antiapoptosis activity of PAI-2 is probably related to its interaction with PSMbeta1.
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PMID:Interaction of plasminogen activator inhibitor-2 and proteasome subunit, beta type 1. 1473 74

FAT10 is an interferon-gamma-inducible ubiquitin-like protein that consists of two ubiquitin-like domains. FAT10 bears a diglycine motif at its C terminus that can form isopeptide bonds to so far unidentified target proteins. Recently we found that FAT10 and its conjugates are rapidly degraded by the proteasome and that the N-terminal fusion of FAT10 to a long lived protein markedly reduces its half-life. FAT10 may hence direct target proteins to the proteasome for degradation. In this study we report a new interaction partner of FAT10 that may link FAT10 to the proteasome. A yeast two-hybrid screen identified NEDD8 ultimate buster-1L (NUB1L) as a non-covalent binding partner of FAT10, and this interaction was confirmed by coimmunoprecipitation and glutathione S-transferase pull-down experiments. NUB1L is also an interferon-inducible protein that has been reported to interact with the ubiquitin-like protein NEDD8, thus leading to accelerated NEDD8 degradation. Here we show that NUB1L binds to FAT10 much stronger than to NEDD8 and that NEDD8 cannot compete with FAT10 for NUB1L binding. The interaction of FAT10 and NUB1L is specific as green fluorescent fusion proteins containing ubiquitin or SUMO-1 do not bind to NUB1L. The coexpression of NUB1L enhanced the degradation rate of FAT10 8-fold, whereas NEDD8 degradation was only accelerated 2-fold. Because NUB1 was shown to bind to the proteasome subunit RPN10 in vitro and to be contained in 26 S proteasome preparations, it may function as a linker that targets FAT10 for degradation by the proteasome.
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PMID:NEDD8 ultimate buster-1L interacts with the ubiquitin-like protein FAT10 and accelerates its degradation. 1475 70

Human papillomaviruses (HPVs) have been recognized as the primary cause of cervical cancer. HPV 16 E7 binds to tumor suppressor retinoblastoma protein, and interferes with its function, causing release of the transcription factor E2F, which influences expression of cell cycle-related genes. This study was performed to identify the genes and proteins modulated by the HPV E7 oncogene. An HPV-negative cervical cancer cell line (C33A) was prepared to establish a stable cell line expressing E7. In order to analyze the target molecules modulated by E7 expression, we used two approaches: matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) and DNA microarrays. Forty-seven spots were identified in C33A/E7 by two-dimensional electrophoresis and MALDI/TOF MS. Protein disulfide isomerase A3, integrase interactor 1 protein, growth inhibitory protein, glutathione S-transferase P, and vav proto-oncogene were down-regulated, whereas heat shock 60 kDa protein 1, Ku70 binding protein, alpha enolase, 26S proteasome subunit were up-regulated. A genomic approach using a microarray kit showed that IL-12R beta 1, cytochrome c, and tumor necrosis factor receptor II were induced by the E7 oncogene. These results suggest that E7 can evade immune surveillance by suppressing or inducing these cell signaling factors, cell cycle regulators, and chaperones.
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PMID:Protein profiling and identification of modulators regulated by the E7 oncogene in the C33A cell line by proteomics and genomics. 1499 4

Homozygous deletion of three nucleotides coding for Ser-171 (S171) of TAL-H (human transaldolase) has been identified in a female patient with liver cirrhosis. Accumulation of sedoheptulose 7-phosphate raised the possibility of TAL (transaldolase) deficiency in this patient. In the present study, we show that the mutant TAL-H gene was effectively transcribed into mRNA, whereas no expression of the TALDeltaS171 protein or enzyme activity was detected in TALDeltaS171 fibroblasts or lymphoblasts. Unlike wild-type TAL-H-GST fusion protein (where GST stands for glutathione S-transferase), TALDeltaS171-GST was solubilized only in the presence of detergents, suggesting that deletion of Ser-171 caused conformational changes. Recombinant TALDeltaS171 had no enzymic activity. TALDeltaS171 was effectively translated in vitro using rabbit reticulocyte lysates, indicating that the absence of TAL-H protein in TALDeltaS171 fibroblasts and lymphoblasts may be attributed primarily to rapid degradation. Treatment with cell-permeable proteasome inhibitors led to the accumulation of TALDeltaS171 in whole cell lysates and cytosolic extracts of patient lymphoblasts, suggesting that deletion of Ser-171 led to rapid degradation by the proteasome. Although the TALDeltaS171 protein became readily detectable in proteasome inhibitor-treated cells, it displayed no appreciable enzymic activity. The results suggest that deletion of Ser-171 leads to inactivation and proteasome-mediated degradation of TAL-H. Since TAL-H is a regulator of apoptosis signal processing, complete deficiency of TAL-H may be relevant for the pathogenesis of liver cirrhosis.
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PMID:Deletion of Ser-171 causes inactivation, proteasome-mediated degradation and complete deficiency of human transaldolase. 1511 36

The level of cellular ceramide, an apoptotic rheostat, is increased by sphingomyelinase or de novo synthesis. The expression of the glutathione S-transferase (GST) gene, whose induction accounts for cell viability, is regulated by activation of CCAAT/enhancer binding protein-beta (C/EBPbeta) and NF-E2-related factor-2 (Nrf2). Hepatic nuclear factor-1 (HNF1) is a transcription factor necessary for cell survival. This study investigated the role of HNF1 in GSTA2 gene transactivation, the ubiquitin proteasomal degradation of HNF1, and the inhibition of activating HNF1 by ceramide for GSTA2 repression. C2-ceramide (C2), a cell-permeable analog, repressed the GSTA2 expression in H4IIE cells, whereas dihydro-C2, an inactive analog, had no effect. Immunoblot, immunocytochemical, and gel shift analyses revealed that C2 decreased the level of nuclear HNF1 and protein binding to the HNF response element (HRE). Deletion of the HRE or the GSTA2 gene promoter region containing the HRE reduced luciferase reporter expression. Immunoprecipitation and immunoblot analyses showed that C2 decreased the level of ubiquitinated HNF1, which was reversed by treatment with MG132, a proteasome inhibitor. C2 suppressed GSTA2 induction by oltipraz via inhibition of inducible HNF1 DNA binding. The functional role of HRE for C2 repression of GSTA2 gene transactivation by oltipraz was verified by both the luciferase reporter gene expression and the transfection experiment with DeltaHNF-pGL-1651 lacking the HRE. C2 similarly repressed the induction of GSTA2 promoter-luciferase by tert-butylhydroquinone via HNF1 suppression, suggesting that constitutive HNF1 activation is required for GSTA2 induction. C2 also inhibited GSTA3/5 expression. In conclusion, the HRE in the GSTA2 promoter region is functionally active for the constitutive and inducible gene expression, and ceramide inhibits GST gene transactivation through decrease in nuclear HNF1, which is degraded by the ubiquitin proteasome system.
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PMID:Ceramide negatively regulates glutathione S-transferase gene transactivation via repression of hepatic nuclear factor-1 that is degraded by the ubiquitin proteasome system. 1515 40

Ceramide is a sphingolipid that acts as a second messenger in signaling systems. Sphingomyelinase generates ceramide in response to cytotoxic stimuli. CCAAT/enhancer binding protein-beta (C/EBPbeta) and NF-E2-related factor-2 (Nrf2) are both involved in the regulation of the genes encoding phase II detoxification enzymes including glutathione S-transferase (GST). In the present study, we examined the effects of ceramide on C/EBPbeta or Nrf2 activation and on the inducible GSTA2 gene transactivation. C2-ceramide (C2), a cell-permeable analog, inhibited GSTA2 induction by oltipraz or tert-butylhydroquinone (t-BHQ) in H4IIE cells, whereas dihydro-C2-ceramide (dihydro-C2), an inactive analog, had no effect. Immunoblot analysis revealed that C2 prevented increase in the level of nuclear C/EBPbeta by oltipraz, whereas the level of C/EBPbeta in total cell lysates was not changed. Increase in nuclear Nrf2 by t-BHQ was also prevented by C2 treatment. Decreases in nuclear C/EBPbeta and Nrf2 by C2 were reversed by treatment of cells with N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132), a proteasome inhibitor, verifying the previous observations that the transcription factors were degraded by the proteasome system. In another study, we found that ceramide decreased nuclear hepatic nuclear factor-1 (HNF1), whose binding to the HNF1-response element in the GSTA2 gene was responsible for the constitutive and inducible gene expression. To define the role of C/EBPbeta or Nrf2 repression in GST expression under the condition excluding the negative regulation by C2-mediated HNF1 suppression, luciferase activity was determined in the cells transfected with DeltaHNF-pGL-1651 plasmid lacking the HNF1-response element. In the cells transfected with DeltaHNF-pGL-1651, C2 decreased the luciferase induction by oltipraz or t-BHQ. Thus, ceramide inhibits C/EBPbeta or Nrf2 activation, which contributes to repression of GSTA2 gene transactivation.
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PMID:Ceramide, an apoptotic rheostat, inhibits CCAAT/enhancer binding protein-beta and NF-E2-related factor-2 activation: the role in glutathione S-transferase A2 gene repression. 1531 26


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