bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Glutathione
S
-Transferase Catalyzes the Dehalogenation of Inhibitory Metabolites of Polychlorinated Biphenyls
Authors: Fortin Pascal D. , Horsman Geoff P. , Yang Hao M. , Eltis Lindsay D. 
Published: June 2006

ABSTRACT

BphK is a glutathione
S
-transferase of unclear physiological function that occurs in some bacterial biphenyl catabolic (
bph
) pathways. We demonstrated that BphK of
Burkholderia xenovorans
strain LB400 catalyzes the dehalogenation of 3-chloro 2-hydroxy-6-oxo-6-phenyl-2,4-dienoates (HOPDAs), compounds that are produced by the cometabolism of polychlorinated biphenyls (PCBs) by the
bph
pathway and that inhibit the pathway's hydrolase. A one-column protocol was developed to purify heterologously produced BphK. The purified enzyme had the greatest specificity for 3-Cl HOPDA (
k
cat
/

K
m

, ∼10
4
M
−1
s
−1
), which it dechlorinated approximately 3 orders of magnitude more efficiently than 4-chlorobenzoate, a previously proposed substrate of BphK. The enzyme also catalyzed the dechlorination of 5-Cl HOPDA and 3,9,11-triCl HOPDA. By contrast, BphK did not detectably transform HOPDA, 4-Cl HOPDA, or chlorinated 2,3-dihydroxybiphenyls. The BphK-catalyzed dehalogenation proceeded via a ternary-complex mechanism and consumed 2 equivalents of glutathione (GSH) (

K
m

for GSH in the presence of 3-Cl HOPDA, ∼0.1 mM). A reaction mechanism consistent with the enzyme's specificity is proposed. The ability of BphK to dehalogenate inhibitory PCB metabolites supports the hypothesis that this enzyme was recruited to facilitate PCB degradation by the
bph
pathway.
Structural Classification of Bacterial Response Regulators: Diversity of Output Domains and Domain Combinations
Authors: Galperin Michael Y. 
Published: June 2006

ABSTRACTCheY-like phosphoacceptor (or receiver [REC]) domain is a common module in a variety of response regulators of the bacterial signal transduction systems. In this work, 4,610 response regulators, encoded in complete genomes of 200 bacterial and archaeal species, were identified and classified by their domain architectures. Previously uncharacterized output domains were analyzed and, in some cases, assigned to known domain families. Transcriptional regulators of the OmpR, NarL, and NtrC families were found to comprise almost 60% of all response regulators; transcriptional regulators with other DNA-binding domains (LytTR, AraC, Spo0A, Fis, YcbB, RpoE, and MerR) account for an additional 6%. The remaining one-third is represented by the stand-alone REC domain (∼14%) and its combinations with a variety of enzymatic (GGDEF, EAL, HD-GYP, CheB, CheC, PP2C, and HisK), RNA-binding (ANTAR and CsrA), protein- or ligand-binding (PAS, GAF, TPR, CAP_ED, and HPt) domains, or newly described domains of unknown function. The diversity of domain architectures and the abundance of alternative domain combinations suggest that fusions between the REC domain and various output domains is a widespread evolutionary mechanism that allows bacterial cells to regulate transcription, enzyme activity, and/or protein-protein interactions in response to environmental challenges. The complete list of response regulators encoded in each of the 200 analyzed genomes is available online athttp://www.ncbi.nlm.nih.gov/Complete_Genomes/RRcensus.html.
Proteomic Analysis ofCampylobacter jejuni11168 Biofilms Reveals a Role for the Motility Complex in Biofilm Formation
Authors: Kalmokoff Martin , Lanthier Patricia , Tremblay Tammy-Lynn , Foss Mary , Lau Peter C. , Sanders Greg , Austin John , Kelly John , Szymanski Christine M. 
Published: June 2006

ABSTRACTCampylobacter jejuniremains the leading cause of bacterial gastroenteritis in developed countries, and yet little is known concerning the mechanisms by which this fastidious organism survives within its environment. We have demonstrated thatC. jejuni11168 can form biofilms on a variety of surfaces. Proteomic analyses of planktonic and biofilm-grown cells demonstrated differences in protein expression profiles between the two growth modes. Proteins involved in the motility complex, including the flagellins (FlaA, FlaB), the filament cap (FliD), the basal body (FlgG, FlgG2), and the chemotactic protein (CheA), all exhibited higher levels of expression in biofilms than found in stationary-phase planktonic cells. Additional proteins with enhanced expression included those involved in the general (GroEL, GroES) and oxidative (Tpx, Ahp) stress responses, two known adhesins (Peb1, FlaC), and proteins involved in biosynthesis, energy generation, and catabolic functions. An aflagellateflhAmutant not only lost the ability to attach to a solid matrix and form a biofilm but could no longer form a pellicle at the air-liquid interface of a liquid culture. Insertional inactivation of genes that affect the flagellar filament (fliA,flaA,flaB,flaG) or the expression of the cell adhesin (flaC) also resulted in a delay in pellicle formation. These findings demonstrate that the flagellar motility complex plays a crucial role in the initial attachment ofC. jejuni11168 to solid surfaces during biofilm formation as well as in the cell-to-cell interactions required for pellicle formation. Continued expression of the motility complex in mature biofilms is unusual and suggests a role for the flagellar apparatus in the biofilm phenotype.
Mnt-Deficient Mammary Glands Exhibit Impaired Involution and Tumors with Characteristics of Myc Overexpression
Authors: Toyo-oka Kazuhito , Bowen Timothy J. , Hirotsune Shinji , Li Zirong , Jain Sonia , Ota Sara , Lozach Laure Escoubet , Bassett Ivan Garcia , Lozach Jean , Rosenfeld Michael G. , Glass Christopher K. , Eisenman Robert , Ren Bing , Hurlin Peter , Wynshaw-Boris Anthony 
Published: June 2006

Abstract
The proto-oncogene c-Myc plays a central role in cell growth and the development of human tumors. c-Myc interacts with Max and Myc-Max complexes bind to E-box and related sequences to activate transcription. Max also interacts with Mnt but Mnt-Max complexes repress transcription when bound to these sequences. MNT maps to human chromosome 17p13.3, a region frequently deleted in various human tumors, including mammary gland tumors. Consistent with the possibility that Mnt functions as a Myc antagonist, Mnt-deficient fibroblasts exhibit many of the hallmark characteristics of cells that overexpress Myc, and conditional (Cre/Lox) inactivation of Mnt in mammary gland epithelium leads to adenocarcinomas. Here, we further characterize mammary gland tissue following conditional deletion of Mnt in the mammary gland. We show that loss of Mnt severely disrupts mammary gland involution and leads to hyperplastic ducts associated with reduced numbers of apoptotic cells. These findings suggest that loss of Mnt in mammary tissue has similarities to Myc overexpression. We tested this directly by using promoter array analysis and mRNA expression analysis by oligonucleotide arrays. We found that Mnt and c-Myc bound to similar promoters in tumors from MMTV-c-Myc transgenic mice, and mRNA expression patterns were similar between mammary tumors from MMTV-Cre/MntKO/CKO and MMTV-c-Myc transgenic mice. These results reveal an important role for Mnt in pregnancy-associated mammary gland development and suggest that mammary gland tumorigenesis in the absence of Mnt is analogous to that caused by Myc deregulation. (Cancer Res 2006; 66(11): 5565-73)
Role of ETS Transcription Factors in the Hypoxia-Inducible Factor-2 Target Gene Selection
Authors: Aprelikova Olga , Wood Matthew , Tackett Sean , Chandramouli Gadisetti V.R. , Barrett J. Carl 
Published: June 2006

Abstract
Tumor hypoxia often directly correlates with aggressive phenotype, metastasis progression, and resistance to chemotherapy. Two transcription factors [hypoxia-inducible factor-1α (HIF-1α) and HIF-2α] are dramatically induced in hypoxic areas and regulate the expression of genes necessary for tumor adaptation to the conditions of low oxygen; however, the relative contribution of these factors is controversial. We used RNA interference–mediated inactivation of HIF-1α or HIF-2α followed by microarray analysis to identify genes specifically regulated by either HIF-1 or HIF-2 in hypoxia. We found that, in the MCF7 cell line, the vast majority of hypoxia-responsive genes (&gt;80%) were dependent on the presence of HIF-1α. However, a small group of genes were preferentially regulated by HIF-2α. Promoter analysis for this group of genes revealed that all of them have putative binding sites for ETS family transcription factors, and 10 of 11 HIF-2α-dependent genes had at least one potential hypoxia-responsive element (HRE) in proximity to an ETS transcription factor binding site. Knockdown of ELK-1, the most often represented member of ETS family, significantly reduced hypoxic induction of the HIF-2α-dependent genes. Physical and functional interaction between ELK-1 and HIF-2α were supported by coimmunoprecipitation of these two proteins, luciferase reporter assay using CITED2 promoter, and binding of ELK-1 protein to the promoters of CITED2 and WISP2 genes in proximity to a HRE. These data suggest that the choice of the target genes by HIF-1 or HIF-2 depends on availability and cooperation of HIFs with other factors recognizing their cognate elements in the promoters. (Cancer Res 2006; 66(11): 5641-7)
Role of Src Kinases in Neu-Induced Tumorigenesis: Challenging the Paradigm Using Csk Homologous Kinase Transgenic Mice
Authors: Kaminski Rafal , Zagozdzon Radoslaw , Fu Yigong , Mroz Pawel , Fu Wei , Seng Seyha , Avraham Shalom , Avraham Hava Karsenty 
Published: June 2006

Abstract
Amplification of the HER-2/neu (ErbB2) gene is observed in ∼30% of human breast cancers, correlating with a poor clinical prognosis. Src kinases are also involved in the etiology of breast cancer, and their activation was suggested to be necessary for Neu-induced oncogenesis. To address whether Src activity is essential for Neu-mediated tumorigenesis, we used a physiologic inhibitor of Src kinase activity, the Csk homologous kinase (CHK), expressed as a mammary tissue-specific transgene. Our data, using a physiologic inhibitor of Src activity (CHK), showed that blocking of Neu-induced Src activity without altering Src expression levels had no significant effects on Neu-mediated mammary tumorigenesis in vivo. This contradicts the current paradigm that activation of Src kinases is essential for Neu-induced oncogenesis. This study is the first to distinguish between the kinase-dependent and kinase-independent actions of Src and shows that its kinase-dependent properties are not requisite for Neu-induced tumorigenesis. (Cancer Res 2006; 66(11): 5757-62)
Dissociation of Angiogenesis and Tumorigenesis in Follistatin- and Activin-Expressing Tumors
Authors: Krneta Jelena , Kroll Jens , Alves Frauke , Prahst Claudia , Sananbenesi Farahnaz , Dullin Christian , Kimmina Sarah , Phillips David J. , Augustin Hellmut G. 
Published: June 2006

Abstract
The transforming growth factor-β superfamily member activin and its antagonist, follistatin, act as a pleiotropic growth factor system that controls cell proliferation, differentiation, and apoptosis. Activin inhibits fibroblast growth factor 2–induced sprouting angiogenesis in vitro (spheroidal angiogenesis assay) and in vivo (Matrigel assay). To further study the role of the activin/follistatin system during angiogenesis and tumor progression, activin- and follistatin-expressing R30C mammary carcinoma cells were studied in mouse tumor experiments. Surprisingly, activin-expressing tumors grew much faster than follistatin-expressing tumors although they failed to induce increased angiogenesis (as evidenced by low microvessel density counts). Conversely, follistatin-expressing tumors were much smaller but had a dense network of small-diameter capillaries. Qualitative angioarchitectural analyses (mural cell recruitment, perfusion) revealed no major functional differences of the tumor neovasculature. Analysis of activin- and follistatin-expressing R30C cells identified a cell autonomous role of this system in controlling tumor cell growth. Whereas proliferation of R30C cells was not altered, follistatin-expressing R30C cells had an enhanced susceptibility to undergo apoptosis. These findings in experimental tumors are complemented by an intriguing case report of a human renal cell carcinoma that similarly shows a dissociation of angiogenesis and tumorigenesis during tumor progression. Collectively, the data shed further light into the dichotomous stimulating and inhibiting roles that the activin/follistatin system can exert during angiogenesis and tumor progression. Furthermore, the experiments provide a critical proof-of-principle example for the dissociation of angiogenesis and tumorigenesis, supporting the concept that tumor growth may not be dependent on increased angiogenesis as long as a minimal intratumoral microvessel density is maintained. (Cancer Res 2006; 66(11): 5686-95)
Synergistic Induction of Folate Receptor β by All-Trans Retinoic Acid and Histone Deacetylase Inhibitors in Acute Myelogenous Leukemia Cells: Mechanism and Utility in Enhancing Selective Growth Inhibition by Antifolates
Authors: Qi Huiling , Ratnam Manohar 
Published: June 2006

Abstract
The folate receptor (FR) type β is a promising target for therapeutic intervention in acute myelogenous leukemia (AML), owing particularly to its selective up-regulation in the leukemic cells by all-trans retinoic acid (ATRA). Here we show, using KG-1 and MV4-11 AML cells and recombinant 293 cells, that the histone deacetylase (HDAC) inhibitors trichostatin A (TSA), valproic acid (VPA), and FK228 potentiated ATRA induction of FR-β gene transcription and FR-β mRNA/protein expression. ATRA and/or TSA did not induce de novo FR synthesis in any of a variety of FR-negative cell lines tested. TSA did not alter the effect of ATRA on the expression of retinoic acid receptor (RAR) α, β, or γ. Chromatin immunoprecipitation assays indicate that HDAC inhibitors act on the FR-β gene by enhancing RAR-associated histone acetylation to increase the association of Sp1 with the basal FR-β promoter. Under these conditions, the expression level of Sp1 is unaltered. A decreased availability of putative repressor AP-1 proteins may also indirectly contribute to the effect of HDAC inhibitors. Finally, FR-β selectively mediated growth inhibition by (6S) dideazatetrahydrofolate in a manner that was greatly potentiated in AML cells by ATRA and HDAC inhibition. Therefore, the combination of ATRA and innocuous HDAC inhibitors may be expected to facilitate selective FR-β–targeted therapies in AML. (Cancer Res 2006; 66(11): 5875-82)
The Histone Deacetylase Inhibitor LBH589 Is a Potent Antimyeloma Agent that Overcomes Drug Resistance
Authors: Maiso Patricia , Carvajal-Vergara Xonia , Ocio Enrique M. , López-Pérez Ricardo , Mateo Gema , Gutiérrez Norma , Atadja Peter , Pandiella Atanasio , San Miguel Jesús F. 
Published: June 2006

AbstractMultiple myeloma represents an incurable disease, for which development of new therapies is required. Here, we report the effect on myeloma cells of LBH589, a new hydroxamic acid–derived histone deacetylase inhibitor. LBH589 was a potent antimyeloma agent (IC50 &lt; 40 nmol/L) on both cell lines and fresh cells from multiple myeloma patients, including cells resistant to conventional chemotherapeutic agents. In addition, LBH589 potentiated the action of drugs, such as bortezomib, dexamethasone, or melphalan. Using gene array, quantitative PCR, and Western analyses, we observed that LBH589 affected a large number of genes involved in cell cycle and cell death pathways. LBH589 blocked cell cycle progression, and this was accompanied by p21, p53, and p57 up-regulation. LBH589 induced cell death through an increase in the mitochondrial outer membrane permeability. LBH589 favored apoptosome formation by inducing cytochrome c release, Apaf-1 up-regulation, and caspase-9 cleavage. In addition, LBH589 stimulated a caspase-independent pathway through the release of AIF from the mitochondria. LBH589 down-regulated Bcl-2 and particularly Bcl-X. Moreover, overexpression of Bcl-X in multiple myeloma cells prevented LBH589-induced cell death. All these data indicate that LBH589 could be a useful drug for the treatment of multiple myeloma patients. (Cancer Res 2006; 66(11): 5781-9)
Recombinant Baculovirus Containing the Diphtheria Toxin A Gene for Malignant Glioma Therapy
Authors: Wang Chao-Yang , Li Feng , Yang Yi , Guo Hai-Yan , Wu Chun-Xiao , Wang Shu 
Published: June 2006

Abstract
Insect baculoviruses are capable of infecting mammalian glial cells in the central nervous system. We investigated in the current study the feasibility of using the viruses as toxin gene vectors to eliminate malignant glioma cells in the brain. We first confirmed that glioma cells were permissive to baculovirus infection, with variable transduction efficiencies at 100 viral particles per cell and ranging between 35% and 70% in seven human and rat glioma cell lines. We then developed a recombinant baculovirus vector accommodating the promoter of glial fibrillary acidic protein (GFAP) to minimize possible side effects caused by overexpression of a therapeutic gene in sensitive neurons. We placed the GFAP promoter into a baculovirus expression cassette, in which the enhancer of human cytomegalovirus immediate-early gene and the inverted terminal repeats of adeno-associated virus were employed to improve the relatively low transcriptional activity of the cellular promoter. This recombinant baculovirus significantly improved transduction in glioma cells, providing the efficiency in C6 rat glioma cells up to 96%. When used to produce the A-chain of diphtheria toxin intracellularly in a rat C6 glioma xenograft model, the baculovirus effectively suppressed tumor development. The new baculovirus vector circumvents some of the inherent problems associated with mammalian viral vectors and provides an additional option for cancer gene therapy. (Cancer Res 2006; 66(11): 5798-806)
CD4+ T-Cell Response to MitochondrialCytochrome bin Human Melanoma
Authors: Voo Kui Shin , Zeng Gang , Mu Jian-Bing , Zhou Juhua , Su Xin-Zhuan , Wang Rong-Fu 
Published: June 2006

AbstractMitochondrial DNA (mtDNA) is highly susceptible to mutations due to the low level of DNA repair and the presence of a high level of reactive oxygen species in the organelle. Although mtDNA mutations have been implicated in degenerating diseases, aging, and cancer, very little is known about the role of T cells in immunosurveillance for mtDNA aberrations. Here, we describe T-cell recognition of a peptide translated from an alternative open reading frame of the mitochondrial cytochrome b (cyt b) gene in melanoma cells established from a patient. To understand how the cyt b gene is transcribed and translated in tumor cells, we found that cyt b–specific CD4+ T cells only recognized protein fractions derived from cytoplasm and not from mitochondria. However, T-cell recognition of tumor cells could be inhibited by treatment of tumor cells with rhodamine 6G inhibitor, which depletes mitochondria. These findings suggest that cyt b mRNA is leaked out of the mitochondria and then translated in the cytoplasm for presentation to CD4+ T cells. The cyt b cDNAs from this patient contain highly heteroplasmic transition mutations compared with control cell lines, suggesting a compromise of mitochondrial integrity that may have contributed to melanoma induction or progression. These findings provide the first example of a mitochondrial immune target for CD4+ T cells and therefore have implications for the immunosurveillance of mitochondrial aberrations in cancer patients. (Cancer Res 2006; 66(11): 5919-26)
Grape Seed Extract Is an Aromatase Inhibitor and a Suppressor of Aromatase Expression
Authors: Kijima Ikuko , Phung Sheryl , Hur Gene , Kwok Sum-Ling , Chen Shiuan 
Published: June 2006

AbstractAromatase is the enzyme that converts androgen to estrogen. It is expressed at higher levels in breast cancer tissues than normal breast tissues. Grape seed extract (GSE) contains high levels of procyanidin dimers that have been shown in our laboratory to be potent inhibitors of aromatase. In this study, GSE was found to inhibit aromatase activity in a dose-dependent manner and reduce androgen-dependent tumor growth in an aromatase-transfected MCF-7 (MCF-7aro) breast cancer xenograft model, agreeing with our previous findings.We have also examined the effect of GSE on aromatase expression. Reverse transcription-PCR experiments showed that treatment with 60 μg/mL of GSE suppressed the levels of exon I.3–, exon PII–, and exon I.6–containing aromatase mRNAs in MCF-7 and SK-BR-3 cells. The levels of exon I.1–containing mRNA, however, did not change with GSE treatment. Transient transfection experiments with luciferase-aromatase promoter I.3/II or I.4 reporter vectors showed the suppression of the promoter activity in a dose-dependent manner. The GSE treatment also led to the down-regulation of two transcription factors, cyclic AMP-responsive element binding protein-1 (CREB-1) and glucocorticoid receptor (GR). CREB-1 and GR are known to up-regulate aromatase gene expression through promoters I.3/II and I.4, respectively. We believe that these results are exciting in that they show GSE to be potentially useful in the prevention/treatment of hormone-dependent breast cancer through the inhibition of aromatase activity as well as its expression. (Cancer Res 2006; 66(11): 5960-7)
Connective Tissue Growth Factor–Specific Monoclonal Antibody Therapy Inhibits Pancreatic Tumor Growth and Metastasis
Authors: Dornhöfer Nadja , Spong Suzanne , Bennewith Kevin , Salim Ali , Klaus Stephen , Kambham Neeraja , Wong Carol , Kaper Fiona , Sutphin Patrick , Nacalumi Rendall , Höckel Michael , Le Quynh , Longaker Michael , Yang George , Koong Albert , Giaccia Amato 
Published: June 2006

Abstract
Pancreatic cancer is highly aggressive and refractory to most existing therapies. Past studies have shown that connective tissue growth factor (CTGF) expression is elevated in human pancreatic adenocarcinomas and some pancreatic cancer cell lines. To address whether and how CTGF influences tumor growth, we generated pancreatic tumor cell lines that overexpress different levels of human CTGF. The effect of CTGF overexpression on cell proliferation was measured in vitro in monolayer culture, suspension culture, or soft agar, and in vivo in tumor xenografts. Although there was no effect of CTGF expression on proliferation in two-dimensional cultures, anchorage-independent growth (AIG) was enhanced. The capacity of CTGF to enhance AIG in vitro was linked to enhanced pancreatic tumor growth in vivo when these cells were implanted s.c. in nude mice. Administration of a neutralizing CTGF-specific monoclonal antibody, FG-3019, had no effect on monolayer cell proliferation, but blocked AIG in soft agar. Consistent with this observation, anti-CTGF treatment of mice bearing established CTGF-expressing tumors abrogated CTGF-dependent tumor growth and inhibited lymph node metastases without any toxicity observed in normal tissue. Together, these studies implicate CTGF as a new target in pancreatic cancer and suggest that inhibition of CTGF with a human monoclonal antibody may control primary and metastatic tumor growth. (Cancer Res 2006; 66(11): 5816-27)