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)

The PHO81 gene is thought to encode an inhibitor of the negative regulators (Pho80p and Pho85p) in the phosphatase (PHO) regulon. Transcription of PHO81 is regulated by Pi signals through the same PHO regulatory system. Elimination of the PHO81 promoter or its substitution by the GAL1 promoter revealed that stimulation of the PHO regulatory system requires both increased transcription of PHO81 and a Pi starvation signal. The predicted Pho81p protein contains 1,179 amino acids (aa) and has six repeats of an ankyrin-like sequence in its central region. The minimum amino acid sequence required for Pho81p function was narrowed down to a 141-aa segment (aa 584 to 724), which contains the fifth and sixth repeats of the ankyrin-like motif. The third to sixth repeats of the ankyrin-like motif of Pho81p have significant similarities to that of p16INK4, which inhibits activity of the human cyclin D-CDK4 kinase complex. Deletion analyses revealed that the N- and C-terminal regions of Pho81p behave as negative and positive regulatory domains, respectively, for the minimal 141-aa region. The negative regulatory activity of the N-terminal domain was antagonized by a C-terminal segment of Pho81p supplied in trans. All four known classes of PHO81c mutations that show repressible acid phosphatase activity in high-Pi medium affect the N-terminal half of Pho81p. An in vitro assay showed that a glutathione S-transferase-Pho81p fusion protein inhibits the Pho85p protein kinase. Association of Pho81p with Pho85p or with the Pho80p-Pho85p complex was demonstrated by the two-hybrid system.
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PMID:Functional domains of Pho81p, an inhibitor of Pho85p protein kinase, in the transduction pathway of Pi signals in Saccharomyces cerevisiae. 782 64

To determine the frequency and clinicopathologic correlates of chromosome 11q13 amplification in breast carcinoma, DNA from 50 invasive tumors was analyzed by Southern blot hybridization using probes for the 11q13 loci bcl-1, PRAD1, hst1, EMS1, and GST-pi, as well as oncogenes c-erbB-2 and c-myc. Sixteen tumors (32%) were amplified for one or more loci. Seven tumors (14%) showed amplification of 11q13 loci; six of these were coamplified with either c-erbB-2 (three), c-myc (two), or both (one). Nine additional tumors (18%) were amplified for c-erbB-2, and three of these were coamplified with c-myc. None showed c-myc amplification alone. Tumors with 11q13 amplification showed equivalent degrees of bcl-1, PRAD1, hst1, and EMS1 amplification, delineating an approximately 800-kb amplicon. GST-pi was inconsistently amplified, evidence that it lies outside the amplicon defined by bcl-1 and EMS1. Amplification of 11q13 was unassociated with patient age, tumor size, axillary lymph node status, hormone receptors, DNA content, histologic grade, mitotic rate, nuclear pleomorphism, or tubule formation. c-myc amplification correlated with the lack of tubule formation (p = 0.04), whereas c-erbB-2 amplification correlated with axillary lymph node positivity (p = 0.04), high histologic grade (p = 0.003), increased nuclear pleomorphism (p = 0.008), and a high mitotic rate (p = 0.02). The frequency of coamplification of 11q13 loci, c-myc, and c-erbB-2 contradicts previous proposals that amplification of these genes occurs in independent subsets of breast carcinoma. Extended clinical followup will be necessary to determine whether 11q13 amplification has prognostic utility in invasive breast cancer.
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PMID:Chromosome 11q13, c-erbB-2, and c-myc amplification in invasive breast carcinoma: clinicopathologic correlations. 790 28

Mouse monoclonal antibodies were produced against the bacterial product encoded by human PRAD1/cyclin D1 gene, which is known to be involved in tumors with translocation or amplification at BCL-1 locus of 11q13. The immunizing antigens used were GST-PRAD1 and T7 gene 10-PRAD1 fusion products. Four antibodies were reactive with both PRAD1 fusion products and cell lysates of B-cell tumor cell lines with t(11;14)(q13;q32) and a breast cancer cell line with 11q13 amplification, on immunoblotting. An immunofluorescence study showed that only one of them stained nuclei of cells with 11q13 abnormalities. Since this antibody proved applicable for conventional paraffin-embedded tissue sections, immunohistologic staining of various lymphoma tissues was performed. Eight of 11 mantle cell lymphomas showed intermediate to strong positivity and 6 of the positive cases demonstrated characteristic staining patterns that were either predominantly nuclear or both nuclear and cytoplasmic. The nuclear staining pattern was not observed with other types of lymphoma and thus may correlate with PRAD1 mRNA overexpression.
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PMID:Monoclonal antibody against PRAD1/cyclin D1 stains nuclei of tumor cells with translocation or amplification at BCL-1 locus. 796 Nov 20

Cyclin E is an important regulator of cell cycle progression that together with cyclin-dependent kinase (cdk) 2 is crucial for the G1/S transition during the mammalian cell cycle. Previously, we showed that severe overexpression of cyclin E protein in tumor cells and tissues results in the appearance of lower molecular weight isoforms of cyclin E, which together with cdk2 can form a kinase complex active throughout the cell cycle. In this study, we report that one of the substrates of this constitutively active cyclin E/cdk2 complex is retinoblastoma susceptibility gene product (pRb) in populations of breast cancer cells and tissues that also overexpress p16. In these tumor cells and tissues, we show that the expression of p16 and pRb is not mutually exclusive. Overexpression of p16 in these cells results in sequestering of cdk4 and cdk6, rendering cyclin D1/cdk complexes inactive. However, pRb appears to be phosphorylated throughout the cell cycle following an initial lag, revealing a time course similar to phosphorylation of glutathione S-transferase retinoblastoma by cyclin E immunoprecipitates prepared from these synchronized cells. Hence, cyclin E kinase complexes can function redundantly and replace the loss of cyclin D-dependent kinase complexes that functionally inactivate pRb. In addition, the constitutively overexpressed cyclin E is also the predominant cyclin found in p107/E2F complexes throughout the tumor, but not the normal, cell cycle. These observations suggest that overexpression of cyclin E in tumor cells, which also overexpress p16, can bypass the cyclin D/cdk4-cdk6/p16/pRb feedback loop, providing yet another mechanism by which tumors can gain a growth advantage.
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PMID:Cyclin E, a redundant cyclin in breast cancer. 898 90

BRCA1, a familial breast and ovarian cancer susceptibility gene encodes nuclear phosphoproteins that function as tumor suppressors in human breast cancer cells. Previously, we have shown that overexpression of a BRCA1 splice variant BRCA1a accelerates apoptosis in human breast cancer cells. In an attempt to determine whether the subcellular localization of BRCA1 is cell cycle regulated, we have studied the subcellular distribution of BRCA1 in asynchronous and growth arrested normal, breast and ovarian cancer cells using different BRCA1 antibodies by immunofluorescence and immunohistochemical staining. Upon serum starvation of NIH3T3, some breast and ovarian cancer cells, most of the BRCA1 protein redistributed to the nucleus revealing a new type of regulation that may modulate the activity of BRCA1 gene. We have also characterized two new variant BRCA1 proteins (BRCA1a/p110 and BRCA1b/ p100) which are phosphoproteins containing phosphotyrosine. Immunofluorescence and Western blotting analysis indicate cytoplasmic and nuclear localization of BRCA1a and BRCA1b proteins. To elucidate the biological function of BRCA1, we created a bacterial fusion protein of glutathione-transferase (GST) and BRCA1 zinc finger domain and detected two cellular proteins with molecular weights of approximately 32 and 65 kD, one of which contains phosphotyrosine designated p32 and p65 BRCA1 interacting proteins (BIP) that specifically interact with BRCA1. Western blot analysis of BIP with cyclins/CDKs and E2F antisera indicated association with cdc2, cdk2, cdk4, cyclin B, cyclin D, cyclin A and E2F-4 but not with cdk3, cdk5, cdk6, E2F-1, E2F-2, E2F-3, E2F-5 and cyclin E. Furthermore, we have also demonstrated a direct interaction of in vitro translated BRCA1a and BRCA1b proteins with recombinant cyclin A, cyclin B1, cyclin D1, cdc2, cdk2 and E2F fusion proteins in vitro. Taken together these results seem to suggest that BRCA1 could be an important negative regulator of cell cycle that functions through interaction with E2F transcriptional factors and phosphorylation by cyclins/cdk complexes with the zinc ring finger functioning as a major protein-protein interaction domain. If the interactions we observe in vitro is also seen in vivo then it may be possible that lack or impaired binding of the disrupted BRCA1 proteins to E2F, cyclins/CDKs in patients with mutations in the zinc finger domain could deprive the cell of an important mechanism for braking cell proliferation leading to the development of breast and ovarian cancers.
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PMID:BRCA1 proteins are transported to the nucleus in the absence of serum and splice variants BRCA1a, BRCA1b are tyrosine phosphoproteins that associate with E2F, cyclins and cyclin dependent kinases. 924 50

We report that cyclin D3/cdk4 kinase activity is regulated by p27(kip1) in BALB/c 3T3 cells. The association of p27(kip1) was found to result in inhibition of cyclin D3 activity as measured by immune complex kinase assays utilizing cyclin D3-specific antibodies. The ternary p27(kip1)/cyclin D3/cdk4 complexes do exhibit kinase activity when measured in immune complex kinase assays utilizing p27(kip1)-specific antibodies. The association of p27(kip1) with cyclin D3 was highest in quiescent cells and declined upon mitogenic stimulation, concomitantly with declines in the total level of p27(kip1) protein. The decline in this association could be elicited by PDGF treatment alone; this was not sufficient, however, for activation of cyclin D3 activity, which also required the presence of factors in platelet-poor plasma in the culturing medium. Unlike cyclin D3 activity, which was detected only in growing cells, p27(kip1) kinase activity was present throughout the cell cycle. Since we found that the p27(kip1) activity was dependent on cyclin D3 and cdk4, we compared the substrate specificity of the active ternary complex containing p27(kip1) and the active cyclin D3 lacking p27(kip1) by tryptic phosphopeptide mapping of GST-Rb phosphorylated in vitro and also by comparing the relative phosphorylation activity toward a panel of peptide substrates. We found that ternary p27(kip1)/cyclin D3/cdk4 complexes exhibited a different specificity than the active binary cyclin D3/cdk4 complexes, suggesting that p27(kip1) has the capacity to both inhibit cyclin D/cdk4 activity as well as to modulate cyclin D3/cdk4 activity by altering its substrate preference.
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PMID:Cyclin D3-associated kinase activity is regulated by p27kip1 in BALB/c 3T3 cells. 969 68

GCIP, a newly identified cyclin D-interacting protein, was found to reduce the phosphorylation of retinoblastoma protein and inhibit E2F1-mediated transcriptional activity. To explore more GCIP interacting proteins, the yeast two-hybrid screening using GCIP as a bait protein was performed. One novel gene, p29, was demonstrated to associate with GCIP in the yeast two-hybrid method and in vitro GST pull-down assay. Multiple tissue Northern blot analysis showed that p29 was abundantly expressed in the heart, skeletal muscle, and kidney relative to other tissues. The transient expression of HA-tagged p29 in HeLa cells localized in the nucleus. Taken together, we have isolated a novel protein, p29, which may be involved in the functional regulation of GCIP.
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PMID:p29, a novel GCIP-interacting protein, localizes in the nucleus. 1111 53

Human p29 has been demonstrated in the yeast two-hybrid method and in vitro GST pull-down assay to associate with GCIP, a cyclin D interacting protein. In this study, we describe the cloning and genomic structure of the mouse homologue, mp29. The overall mouse mp29 amino acid sequence is highly identical (91%) to human p29. Polyclonal antibody against mp29 was raised and the subcellular localization of mp29 was identified to be in the nucleus. Genomic clones containing mp29 gene were isolated and this gene was divided into seven exons spanning 9kb of genomic DNA. The transcription initiation site of mp29 gene was determined to be 94bp upstream of the translation initiation codon and the first 140bp proximal TATA-less promoter region is required to activate minimal transcription of mouse mp29 gene in mammalian cells.
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PMID:Cloning, expression, and genomic organization of mouse mp29 gene. 1243 76

Basic research and clinical chemoprevention trials support the protective role of selenium in cancer prevention but the mechanisms based on the molecular level remain to be fully defined. This mini-review focuses only on the elucidation of the molecular mechanisms of cancer prevention by selenium using the genomics approach; target organs discussed here are breast, prostate, colon and lung. The results described here support the utility of microarray technology in delineating the molecular mechanisms of cancer prevention by selenium. These results are based on studies employing human and rodent cell lines and tissues from animal models ranging from normal to frank cancer. The dose and the form of selenium are determining factors in cancer chemoprevention. The results of the microarray analysis reviewed here indicate that selenium, independent of its form and the target organ examined, alters several genes in a manner that can account for cancer prevention. Selenium can up regulate genes related to phase II detoxification enzymes, certain selenium-binding proteins and select apoptotic genes, while down regulating those related to phase I activating enzymes and cell proliferation. Independent of tissue type, selenium arrests cells in G1 phase of cell cycle, inhibits CYCLIN A, CYCLIN D1, CDC25A, CDK4, PCNA and E2F gene expressions while induces the expressions of P19, P21, P53, GST, SOD, NQO1, GADD153 and certain CASPASES. In addition to those described above, genes such as OPN, which is mainly involved in metastasis and recently reported to be down regulated by selenium, should be considered as potential molecular marker in clinical chemoprevention trials. Collectively, literature data indicate that some of these genes that were altered by selenium are also involved in the development of human cancers described in this review. It appears that androgen receptor status may influence the effect of selenium on gene expression profile in prostate cancer; whether estrogen receptor may influence the effect of selenium on gene expression in breast cancer requires further studies. Knowledge from gene array data in combination with proteomics approaches, using homogenous population of cell types with the aid of laser capture microdissection, may provide an individualized dimension of information on cancer risk and potential targets for its prevention. The molecular (genetic) biomarkers presented in this review will provide the foundation for future studies of the chemopreventive properties of structurally varied selenium compounds.
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PMID:Molecular chemoprevention by selenium: a genomic approach. 1609 79

Tobacco (Nicotiana tabacum L.) cv Bright Yellow-2 (BY-2) cells are the most highly synchronizable plant cell culture, and previously we used them to analyze cell cycle regulation of cyclin-dependent kinases (CDKs) containing the cyclin binding motifs PSTAIRE (CDKA) and PPTA/TLRE (CDKB). Here we describe the analysis of tobacco CycD3 cyclins whose transcripts predominantly accumulate during G2 to M phase, which represents a unique feature of this type of cyclin D in plants. Although protein levels of CycD3s fluctuate with different patterns during the cell cycle, kinase assays revealed that the CycD3-associated kinases phosphorylate histone H1 and the tobacco retinoblastoma related protein (NtRBR1) with two peaks at the G1/S and G2/M boundaries. In vitro pull-down assays revealed that cell cycle-regulated CycD3s bind to CDKA, but more weakly than does CycD3;3, and that they also bind to CDKB and the CDK inhibitor NtKIS1a. Mutations in the cyclin box of the CycD3s showed that two amino acids are required for binding with CDKA and NtKIS1a, but no diminished interaction was observed with CDKB. A reconstituted kinase assay was adapted for use with bacterially produced GST-CycD3s, and kinase activity could be activated by incubation of extracts from exponentially growing BY-2 cells. Such activated complexes contained CDKA and CDKB, and the reconstituted GST-CycD3 mutants, retaining binding ability to CDKB, showed kinase activity, suggesting that these cell cycle-regulated CycD3s form active complexes with both A- and B-type CDKs in vitro.
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PMID:Cell cycle regulated D3-type cyclins form active complexes with plant-specific B-type cyclin-dependent kinase in vitro. 1678 9


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