bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Cellular 2′-5′ Oligoadenylate Synthetase by the Herpes Simplex Virus Type 1 Us11 Protein
Authors: Sànchez Ricardo , Mohr Ian 
Published: January 2007

ABSTRACT

Among the many host genes induced by virus infection and interferon, the eIF2α protein kinase PKR and the 2′-5′ oligoadenylate synthetase (OAS) are both activated by double-stranded RNA (dsRNA) produced in virus-infected cells. Furthermore, each is a critical component that independently acts to inhibit virus replication and thereby contributes to the establishment of an antiviral state. As part of their tactics to foil host defense mechanisms, some viruses prevent the induction of interferon-responsive genes at the level of transcription. Other viruses, such as herpes simplex virus type 1 (HSV-1), can additionally replicate in interferon-treated cells and must also evade the actions of host defense proteins such as PKR and OAS that have been previously synthesized and merely await detection of an activating signal. Whereas HSV-1 gene products γ
1
34.5 and Us11 are required for viral replication in interferon-treated cells and both act in a temporally coordinated manner during infection to counteract PKR, HSV-1 functions that target OAS have not been described. Here, we demonstrate that HSV-1 infection inhibits 2′-5′ oligoadenylate synthesis in interferon-stimulated primary human cells. The OAS-inhibiting activity is generated late in the virus' productive life cycle and requires the Us11 gene product. Moreover, we establish that the Us11 protein is sufficient to block OAS activation in extracts from uninfected, interferon-treated cells. Inhibition of OAS specifically requires the Us11 dsRNA-binding domain, suggesting a mechanism that, in part, relies on sequestering available dsRNA produced during infection. Thus, in addition to PKR and its protein activator, PACT, the HSV-1 Us11 gene product is able to counteract the activity of OAS, a third cellular protein critical for host defense.
Immediate Activation Fails To Rescue Efficient Human Immunodeficiency Virus Replication in Quiescent CD4+T Cells
Authors: Vatakis Dimitrios N. , Bristol Gregory , Wilkinson Thomas A. , Chow Samson A. , Zack Jerome A. 
Published: January 2007

ABSTRACTUnlike activated T cells, quiescent CD4+T cells have shown resistance to human immunodeficiency virus (HIV) infection due to a block in the early events of the viral life cycle. To further investigate the nature of this block, we infected quiescent CD4+T cells with HIV-1NL4-3and immediately stimulated them. Compared to activated (prestimulated) cells, these poststimulated cells showed slightly decreased viral entry and delays in the completion of reverse transcription. However, the relative efficiency of integration was similar to that of prestimulated cells. Together, this resulted in decreased expression oftat/revmRNA and synthesis of viral protein. Furthermore, based on cell cycle staining and BrdU incorporation, poststimulated cells expressing viral protein failed to initiate a second round of their cell cycle, independently of Vpr-mediated arrest. Together, these data demonstrate that the early stages of the HIV life cycle are inefficient in these poststimulated cells and that efficient replication cannot be induced by subsequent activation.
A Second Receptor Binding Site on Human Parainfluenza Virus Type 3 Hemagglutinin-Neuraminidase Contributes to Activation of the FusionMechanism
Authors: Porotto Matteo , Fornabaio Micaela , Kellogg Glen E. , Moscona Anne 
Published: January 2007

ABSTRACT
The
hemagglutinin-neuraminidase (HN) protein of paramyxoviruses carries out
three discrete activities that each affect the ability of HN to promote
viral fusion and entry: receptor binding, receptor cleaving
(neuraminidase), and triggering of the fusion protein. The
interrelationship between the receptor binding and fusion-triggering
functions of HN has not been clear. For human parainfluenza type 3
(HPIV3), one bifunctional site on HN can carry out both receptor
binding and neuraminidase activities, and this site's receptor binding
can be inhibited by the small receptor analog zanamivir. We now report
experimental evidence, complemented by computational data, for a second
receptor binding site near the HPIV3 HN dimer interface. This second
binding site can mediate receptor binding even in the presence of
zanamivir, and it differs from the second receptor binding site of the
paramyxovirus Newcastle disease virus in its function and its
relationship to the primary binding site. This second binding site of
HPIV3 HN is involved in triggering F. We suggest that the two
receptor binding sites on HPIV3 HN each contribute in distinct ways to
virus-cell interaction; one is the multifunctional site that contains
both binding and neuraminidase activities, and the other contains
binding activity and also is involved in fusion
promotion.
SULFUR ADSORPTION ON THE GOETHITE (110) SURFACE
Authors: SIMONETTI S. , DAMIANI D. , BRIZUELA G. , JUAN A. 
Published: January 2007

The electronic structure of S adsorption on goethite (110) surface has been studied by ASED-MO cluster calculations. For S location, the most exposed surface atoms of goethite surface were selected. The calculations show that the surface offers several places for S adsorption. The most energetically stable system corresponds to S location above H atom.We studied in detail the configurations that correspond to the higher OP values. For these configurations, the H-S and Fe-S computed distances are 2.1 and 3.7 Å, respectively. The H-S and Fe-S are mainly bonding interaction with OP values of 0.156 and 0.034, respectively. The Fe-S interaction mainly involves Fe 3dx2-y2atomic orbitals with lesser participation of Fe 4pyand Fe 3dyzatomic orbitals. The O-S interaction shows the same bonding and antibonding contributions giving a small OP value. The O-S interaction involves O 2p orbitals. There is an electron transfer to the Fe atom from the S atom. On the other hand, there is an electron transfer to S atom from the H and O atoms, respectively.
Epidermal Growth Factor Receptor Signaling Is Required for Microadenoma Formation in the Mouse Azoxymethane Model of Colonic Carcinogenesis
Authors: Fichera Alessandro , Little Nathaniel , Jagadeeswaran Sujatha , Dougherty Urszula , Sehdev Amikar , Mustafi Reba , Cerda Sonia , Yuan Weihua , Khare Sharad , Tretiakova Maria , Gong Can , Tallerico Michael , Cohen Greg , Joseph Loren , Hart John , Turner Jerrold R. , Bissonnette Marc 
Published: January 2007

Abstract
Colonic carcinogenesis involves the progressive dysregulation of homeostatic mechanisms that control growth. The epidermal growth factor (EGF) receptor (EGFR) regulates colonocyte growth and differentiation and is overexpressed in many human colon cancers. A requirement for EGFR in colonic premalignancy, however, has not been shown. In the current study, we used a specific EGFR antagonist, gefitinib, to investigate this role of the receptor in azoxymethane colonic premalignancy. The azoxymethane model shares many clinical, histologic, and molecular features of human colon cancer. Mice received azoxymethane i.p. (5 mg/kg/wk) or saline for 6 weeks. Animals were also gavaged with gefitinib (10 mg/kg body weight) or vehicle (DMSO) thrice weekly for 18 weeks, a dose schedule that inhibited normal receptor activation by exogenous EGF. Compared with control colonocytes [bromodeoxyuridine (BrdUrd), 2.2 ± 1.2%], azoxymethane significantly increased proliferation (BrdUrd, 12.6 ± 2.8%), whereas gefitinib inhibited this hyperproliferation (BrdUrd, 6.2 ± 4.0%; &lt;0.005). Azoxymethane significantly induced pro-transforming growth factor-α (6.4 ± 1.3–fold) and increased phospho-(active) EGFR (5.9 ± 1.1–fold), phospho-(active) ErbB2 (2.3 ± 0.2–fold), and phospho-(active) extracellular signal-regulated kinase (3.3 ± 0.4–fold) in premalignant colonocytes. Gefitinib inhibited activations of these kinases by &gt;75% (P &lt; 0.05). Gefitinib also significantly reduced the number of large aberrant crypt foci and decreased the incidence of colonic microadenomas from 75% to 33% (P &lt; 0.05). Gefitinib concomitantly decreased cell cycle–regulating cyclin D1 and prostanoid biosynthetic enzyme cyclooxygenase-2 in microadenomas, suggesting that these regulators are key targets of EGFR in colonic carcinogenesis. These results show for the first time that EGFR signaling is required for early stages of colonic carcinogenesis. Our findings suggest, moreover, that inhibitors of EGFR might be useful in chemopreventive strategies in individuals at increased risk for colonic malignancies. [Cancer Res 2007;67(2):827–35]
Nestin Is Expressed in the Basal/Myoepithelial Layer of the Mammary Gland and Is a Selective Marker of Basal Epithelial Breast Tumors
Authors: Li Hua , Cherukuri Pratima , Li Na , Cowling Victoria , Spinella Michael , Cole Michael , Godwin Andrew K. , Wells Wendy , DiRenzo James 
Published: January 2007

Abstract
Transcriptional profiling has identified five breast cancer subtypes, of which the basal epithelial is most aggressive and correlates with poor prognosis. These tumors display a high degree of cellular heterogeneity and lack established molecular targets, such as estrogen receptor-α, progesterone receptor, and Her2 overexpression, indicating a need for definitive diagnostic markers. We present evidence that nestin, a previously described marker of regenerative cells in diverse tissues, is expressed in the regenerative compartment of the normal human mammary gland. Colocalization studies indicate two distinct populations of mammary epithelia that express nestin: one expressing cytokeratin 14 (CK14) and ΔN-p63 and another expressing desmin. Immunohistochemical analysis indicates that ΔN-p63 and nestin are coordinately expressed during pregnancy in the murine mammary gland. In the embryonal carcinoma cell line NT2/D1, ectopic ΔN-p63-α disrupts retinoic acid–induced differentiation, thereby preserving expression of nestin; however, small interfering RNA–mediated ablation of nestin is insufficient to promote differentiation, indicating that whereas nestin may identify cells within the regenerative compartment of the mammary gland, it is insufficient to block differentiation and preserve replicative capacity. Immunohistochemical analysis of basal epithelial breast tumors, including those shown to carry BRCA1 mutations, indicates robust expression of nestin and CK14, punctate expression of p63, and low to undetectable levels of desmin expression. Nestin was not detected in other breast cancer subtypes, indicating selectivity for basal epithelial breast tumors. These studies identify nestin as a selective marker of the basal breast cancer phenotype, which displays features of mammary progenitors. [Cancer Res 2007;67(2):501–10]
Stromal-Epithelial Cell Interactions and Androgen Receptor-Coregulator Recruitment Is Altered in the Tissue Microenvironment of Prostate Cancer
Authors: Cano Patricia , Godoy Alejandro , Escamilla Rosalba , Dhir Rajiv , Onate Sergio A. 
Published: January 2007

Abstract
Tissue recombination experiments show that prostate mesenchyma directs prostate epithelial cell growth and development in an androgen-dependent manner, and that functional differentiation of prostate epithelium requires androgen-driven processes in both epithelia and stroma. The androgen induction of target genes in primary cultures of prostate stromal and epithelial cells was determined using an adenoviral expression system, which employed the MMTV-enhancer driven luciferase reporter as an androgen receptor (AR)–mediated transcription assay. These studies indicate that both cell types contain functional AR. Androgen induction of luciferase reporter activity is 3-fold in stromal cells compared with 10-fold in epithelial cells. AR-mediated transcription activity in stroma cells was enhanced by coculture with epithelial cells or epithelial cell–conditioned media. The elevated AR-mediated transcription activity in stromal cells that were exposed to epithelial factors correlated with increased recruitment of coactivators to the AR transcriptional complex. Epithelial cells facilitated interactions of AR with SRC-1 in an androgen-dependent manner. However, AR-mediated transcriptional activity in stromal cells isolated from prostate cancer was reduced compared with stromal cells isolated from benign prostate and continued to be reduced when cocultured with tumor-derived prostate epithelial cells. The occupancy of AR and coregulators on target genes showed that androgen-bound AR in prostate cancer stromal cells was associated with the corepressor silencing mediator for retinoid and thyroid hormone receptor. Thus, the ability of epithelial cells to modulate coregulator recruitment to the AR transcriptional complex on androgen-responsive genes seems altered in the stromal microenvironment of prostate cancer. [Cancer Res 2007;67(2):511–9]
Heat Shock Protein 70 Increases Tumorigenicity and Inhibits Apoptosis in Pancreatic Adenocarcinoma
Authors: Aghdassi Ali , Phillips Phoebe , Dudeja Vikas , Dhaulakhandi Dhara , Sharif Rifat , Dawra Rajinder , Lerch Markus M. , Saluja Ashok 
Published: January 2007

AbstractPancreatic carcinoma is a malignant disease that responds poorly to chemotherapy because of its resistance to apoptosis. Heat shock proteins (Hsp) are not only cytoprotective but also interfere with the apoptotic cascade. Here, we investigated the role of Hsp70 in regulating apoptosis in pancreatic cancer cells. Hsp70 expression was increased in pancreatic cancer cells compared with normal pancreatic ductal cells. This was confirmed by increased mRNA levels for Hsp70 in human pancreatic cancer tissue compared with neighboring normal tissue from the same patient. Depletion of Hsp70 by quercetin decreased cell viability and induced apoptosis in cancer cells but not in normal pancreatic ductal cells. To show that this is a specific effect of Hsp70 on apoptosis, levels of Hsp70 were knocked down by short interfering RNA treatment, which also induced apoptosis in cancer cells as indicated by Annexin V staining and caspase activation. Daily administration of quercetin to nude mice decreased tumor size as well as Hsp70 levels in tumor tissue. These findings indicate that Hsp70 plays an important role in apoptosis and that selective Hsp70 knockdown can be used to induce apoptosis in pancreatic cancer cells. [Cancer Res 2007;67(2):616–25]
SOX9 Is Expressed in Normal Prostate Basal Cells and Regulates Androgen Receptor Expression in Prostate Cancer Cells
Authors: Wang Hongyun , McKnight Nicole C. , Zhang Tao , Lu Michael L. , Balk Steven P. , Yuan Xin 
Published: January 2007

Abstract
SOX9 is a member of the SOX [Sry-related high-mobility group (HMG) box] family of HMG DNA-binding domain transcription factors and is required for the development and differentiation of multiple cell lineages. This report shows that basal epithelial cells express SOX9 in normal prostate, with no detectable expression in luminal epithelial cells. In contrast, SOX9 is expressed in primary prostate cancers in vivo, at a higher frequency in recurrent prostate cancer and in prostate cancer cell lines (LNCaP, CWR22, PC3, and DU145). SOX9 message and protein levels in prostate cancer cells were increased by treatment with glycogen synthase kinase 3β inhibitor (SB415286), and SOX9 was reduced when β-catenin was down-regulated by small interfering RNA (siRNA), indicating that SOX9 expression in prostate cancer is regulated by Wnt/β-catenin signaling. SOX9 bound specifically to androgen receptor (AR) DNA-binding domain glutathione S-transferase fusion proteins, and this interaction was dependent on a short peptide immediately COOH-terminal to the DNA-binding domain (the C-terminal extension), which is required for interactions between steroid hormone receptors and the architectural HMG proteins. Exogenous SOX9 expressed at high nonphysiologic levels decreased AR expression and activity; however, at lower levels, SOX9 increased AR protein expression. Significantly, down-regulation of SOX9 by siRNA in prostate cancer cells reduced endogenous AR protein levels, and cell growth indicating that SOX9 contributes to AR regulation and decreased cellular proliferation. These results indicate that SOX9 in prostate basal cells supports the development and maintenance of the luminal epithelium and that a subset of prostate cancer cells may escape basal cell requirements through SOX9 expression. [Cancer Res 2007;67(2):528–36]
Adenovirus-Mediated Expression of a Dominant Negative Ku70 Fragment Radiosensitizes Human Tumor Cells under Aerobic and Hypoxic Conditions
Authors: He Fuqiu , Li Ligeng , Kim Dooha , Wen Bixiu , Deng Xuelong , Gutin Philip H. , Ling Clifton C. , Li Gloria C. 
Published: January 2007

Abstract
Ku70 is one component of a protein complex, the Ku70/Ku80 heterodimer, which binds to DNA double-strand breaks and activates DNA-dependent protein kinase (DNA-PK), leading to DNA damage repair. Our previous work has confirmed that Ku70 is important for DNA damage repair in that Ku70 deficiency compromises the ability of cells to repair DNA double-strand breaks, increases the radiosensitivity of cells, and enhances radiation-induced apoptosis. Because of the radioresistance of some human cancers, particularly glioblastoma, we examined the use of a radio-gene therapy paradigm to sensitize cells to ionizing radiation. Based on the analysis of the structure-function of Ku70 and the crystal structure of Ku70/Ku80 heterodimer, we designed and identified a candidate dominant negative fragment involving an NH2-terminal deletion, and designated it as DNKu70. We generated this mutant construct, stably overexpressed it in Rat-1 cells, and showed that it has a dominant negative effect (i.e., DNKu70 overexpression results in decreased Ku-DNA end-binding activity, and increases radiosensitivity). We then constructed and generated recombinant replication-defective adenovirus, with DNKu70 controlled by the cytomegalovirus promoter, and infected human glioma U-87 MG cells and human colorectal tumor HCT-8 cells. We show that the infected cells significantly express DNKu70 and are greatly radiosensitized under both aerobic and hypoxic conditions. The functional ramification of DNKu70 was further shown in vivo: expression of DNKu70 inhibits radiation-induced DNA-PK catalytic subunit autophosphorylation and prolongs the persistence of γ-H2AX foci. If radiation-resistant tumor cells could be sensitized by down-regulating the cellular level/activity of Ku/DNA-PK, this approach could be evaluated as an adjuvant to radiation therapy. [Cancer Res 2007;67(2):634–42]
Bortezomib Inhibits Cell-Cell Adhesion and Cell Migration and Enhances Epidermal Growth Factor Receptor Inhibitor–Induced Cell Death in Squamous Cell Cancer
Authors: Lorch Jochen H. , Thomas Tarita O. , Schmoll Hans-Joachim 
Published: January 2007

Abstract
The lack of cell-cell adhesion and increased migration are key characteristics of cancer cells. The loss of expression of cell adhesion components and overexpression of components critical for cell migration, such as focal adhesion kinase (FAK), correlate with poor prognosis. Because alteration of protein turnover affects the expression levels and, in turn, may influence protein function, we investigated the effects of the proteasome inhibitor bortezomib on cell adhesion and migration in oral squamous cell cancer cell lines SCC68 and SCC15. Following treatment with bortezomib, protein levels of adherens junction components such as E-cadherin were unchanged. The desmosomal linker protein desmoplakin level was increased, whereas the protein level of the desmosomal cadherin, desmoglein 2, was diminished. Reduced desmoglein 2 levels correlated with the diminished strength of mechanical cell-cell adhesion. The protein level of the epidermal growth factor receptor (EGFR) increased after proteasome inhibition and EGFR inhibition with the EGFR-specific tyrosine kinase inhibitor PKI166 was able to restore cell-cell adhesion. Furthermore, we found that the combination of PKI166 with bortezomib enhanced the rate of cell death. Although the FAK protein level was unchanged following bortezomib treatment, recruitment of FAK phosphorylated at tyrosine residue 397 to the periphery of the cell was induced. Migration was reduced following treatment with bortezomib, which could potentially be explained by a prominent but disorganized actin fiber network revealed through immunofluorescence. Collectively, our results suggest that proteasome inhibition using bortezomib affects cell adhesion and cell migration profoundly and provides a rationale for its clinical use in conjunction with an EGFR inhibitor. [Cancer Res 2007;67(2):727–34]
Activation of Akt Predicts Poor Outcome in Neuroblastoma
Authors: Opel Daniela , Poremba Christopher , Simon Thorsten , Debatin Klaus-Michael , Fulda Simone 
Published: January 2007

Abstract
Whereas aberrant activation of the phosphatidylinositol 3′-kinase (PI3K)/Akt pathway, a key survival cascade, has previously been linked to poor prognosis in several human malignancies, its prognostic effect in neuroblastoma has not yet been explored. We therefore investigated the phosphorylation status of Akt, S6 ribosomal protein as target of mammalian target of rapamycin, and extracellular signal–regulated kinase (ERK) in 116 primary neuroblastoma samples by tissue microarray and its correlation with established prognostic markers and survival outcome. Here, we provide for the first time evidence that phosphorylation of Akt at serine 473 (S473) and/or threonine 308 (T308), S6 ribosomal protein, and ERK frequently occurs in primary neuroblastoma. Importantly, we identified Akt activation as a novel prognostic indicator of decreased event-free or overall survival in neuroblastoma, whereas phosphorylation of S6 ribosomal protein or ERK had no prognostic effect. In addition, Akt activation correlated with variables of aggressive disease, including MYCN amplification, 1p36 aberrations, advanced disease stage, age at diagnosis, and unfavorable histology. Monitoring Akt at T308 or both phosphorylation sites improved the prognostic significance of Akt activation in neuroblastoma specimens compared with S473 phosphorylation. Parallel experiments in neuroblastoma cell lines revealed that activation of Akt by insulin-like growth factor (IGF)-I significantly inhibited tumor necrosis factor–related apoptosis-inducing ligand– or chemotherapy-induced apoptosis in a PI3K-dependent manner because the PI3K inhibitor LY294002 completely reversed the IGF-I–mediated protection of neuroblastoma cells from apoptosis. By showing that activation of Akt correlates with poor prognosis in primary neuroblastoma in vivo and with apoptosis resistance in vitro, our findings indicate that Akt presents a clinically relevant target in neuroblastoma that warrants further investigation. [Cancer Res 2007;67(2):735–45]