bluuebunny/crossref_metadata_2025_split huggingface dataset:
Angiopoietin 1 Is Mitogenic for Cultured Endothelial Cells
Authors: Kanda Shigeru , Miyata Yasuyoshi , Mochizuki Yasushi , Matsuyama Toshifumi , Kanetake Hiroshi 
Published: September 2005

Abstract
The angiopoietin (Ang)/Tie2 system is implicated in blood vessel formation and maturation. However, the mitogenic effects of angiopoietins remain to be elucidated. Here, we show that Ang1 is mitogenic for cultured endothelial cells. Ang1 dose-dependently induced the proliferation and increased the labeling index of a murine brain capillary endothelial cell line, IBE cells. Ang1 also increased the labeling index of human umbilical vein endothelial cells (HUVEC). Ang1 up-regulated the expression of cyclin D1 in both of these cells. Ang1 activated mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) in IBE cells and HUVECs. Activated PI3K was associated with c-Fes protein tyrosine kinase in these cells, but not with Tie2. p70 S6 kinase (p70 S6K) was activated by Ang1-treatment, although this activation was blocked by a PI3K inhibitor, LY294002. Simultaneous treatment of cells with PD98059 (MAPK/extracellular regulated kinase kinase inhibitor) and rapamycin (mTOR inhibitor) completely blocked Ang1-induced mitogenic activity for IBE cells and HUVECs. Although Ang2 at high concentration weakly activated Tie2 and p70 S6K, it failed to activate Ras and MAPK, or to induce cell proliferation. Taken together, these findings indicate that Ang1 exerts mitogenic activity on endothelial cells, which requires activation of both MAPK and p70 S6K.
The Myc Target Gene JPO1/CDCA7 Is Frequently Overexpressed in Human Tumors and Has Limited Transforming Activity In vivo
Authors: Osthus Rebecca C. , Karim Baktiar , Prescott Julia E. , Smith B. Douglas , McDevitt Michael , Huso David L. , Dang Chi V. 
Published: September 2005

Abstract
MYC is frequently overexpressed in human cancers, but the downstream events contributing to tumorigenesis remain incompletely understood. MYC encodes an oncogenic transcription factor, of which target genes presumably contribute to cellular transformation. Although Myc regulates about 15% of genes and combinations of target genes are likely required for tumorigenesis, we studied in depth the expression of the Myc target gene, JPO1/CDCA7, in human cancers and its ability to provoke tumorigenesis in transgenic mice. JPO1/CDCA7 is frequently overexpressed in human cancers, and in particular, its expression is highly elevated in chronic myelogenous leukemia blast crisis as compared with the chronic phase. In murine lymphoid tissues, ectopic human JPO1/CDCA7 expression resulted in a 2-fold increased risk of lymphoid malignancies at 1 year. The transgene, which was driven by the H2-K promoter, exhibited leaky expression in nonlymphoid tissues such as kidney. We observed a significant increased incidence of transgenic animal solid tumors, which were not seen in littermate controls. These observations suggest that JPO1/CDCA7 may contribute to Myc-mediated tumorigenesis.
Human T-Cell Leukemia Virus Type I at Age 25: A Progress Report
Authors: Matsuoka Masao , Jeang Kuan-Teh 
Published: September 2005

AbstractIt has been 25 years since the discovery of human T-cell leukemia virus type I (HTLV-I) and its role in adult T-cell leukemia. Here, in brief, we review the current state of our understanding of HTLV-I epidemiology, viral biology, pathogenesis, and treatment. We discuss how HTLV-I may transform cells through destabilization of cellular genomic integrity and induction of cellular tolerance for chromosomal errors.
A Mouse Model for the Carney Complex Tumor Syndrome Develops Neoplasia in Cyclic AMP–Responsive Tissues
Authors: Kirschner Lawrence S. , Kusewitt Donna F. , Matyakhina Ludmila , Towns William H. , Carney J. Aidan , Westphal Heiner , Stratakis Constantine A. 
Published: September 2005

AbstractCarney complex is an autosomal dominant neoplasia syndrome characterized by spotty skin pigmentation, myxomatosis, endocrine tumors, and schwannomas. This condition may be caused by inactivating mutations in PRKAR1A, the gene encoding the type 1A regulatory subunit of protein kinase A. To better understand the mechanism by which PRKAR1A mutations cause disease, we have developed conventional and conditional null alleles for Prkar1a in the mouse. Prkar1a+/− mice developed nonpigmented schwannomas and fibro-osseous bone lesions beginning at ∼6 months of age. Although genotype-specific cardiac and adrenal lesions were not seen, benign and malignant thyroid neoplasias were observed in older mice. This spectrum of tumors overlaps that seen in Carney complex patients, confirming the validity of this mouse model. Genetic analysis indicated that allelic loss occurred in a subset of tumor cells, suggesting that complete loss of Prkar1a plays a key role in tumorigenesis. Similarly, tissue-specific ablation of Prkar1a from a subset of facial neural crest cells caused the formation of schwannomas with divergent differentiation. These observations confirm the identity of PRKAR1A as a tumor suppressor gene with specific importance to cyclic AMP–responsive tissues and suggest that these mice may be valuable tools not only for understanding endocrine tumorigenesis but also for understanding inherited predispositions for schwannoma formation.
A Novel Human tRNA-Dihydrouridine Synthase Involved in Pulmonary Carcinogenesis
Authors: Kato Tatsuya , Daigo Yataro , Hayama Satoshi , Ishikawa Nobuhisa , Yamabuki Takumi , Ito Tomoo , Miyamoto Masaki , Kondo Satoshi , Nakamura Yusuke 
Published: September 2005

Abstract
An increased level of dihydrouridine in tRNAPhe was found in human malignant tissues nearly three decades ago, but its biological significance in carcinogenesis has remained unclear. Through analysis of genome-wide gene-expression profiles among non–small cell lung carcinomas (NSCLC), we identified overexpression of a novel human gene, termed hDUS2, encoding a protein that shared structural features with tRNA-dihydrouridine synthases (DUS). The deduced 493-amino-acid sequence showed 39% homology to the dihydrouridine synthase 2 enzyme (Dus2) of Saccharomycescerevisiae and contained a conserved double-strand RNA-binding motif (DSRM). We found that hDUS2 protein had tRNA-DUS activity and that it physically interacted with EPRS, a glutamyl-prolyl tRNA synthetase, and was likely to enhance translational efficiencies. A small interfering RNA against hDUS2 transfected into NSCLC cells suppressed expression of the gene, reduced the amount of dihydrouridine in tRNA molecules, and suppressed growth. Immunohistochemical analysis showed significant association between higher levels of hDUS2 in tumors and poorer prognosis of lung cancer patients. Our data imply that up-regulation of hDUS2 is a relatively common feature of pulmonary carcinogenesis and that selective suppression of hDUS2 enzyme activity and/or inhibition of formation of the hDUS2-tRNA synthetase complex could be a promising therapeutic strategy for treatment of many lung cancers.
Proteasome Inhibitor MG132 Induces Death Receptor 5 through CCAAT/Enhancer-Binding Protein Homologous Protein
Authors: Yoshida Tatsushi , Shiraishi Takumi , Nakata Susumu , Horinaka Mano , Wakada Miki , Mizutani Yoichi , Miki Tsuneharu , Sakai Toshiyuki 
Published: September 2005

Abstract
Combined treatment with a proteasome inhibitor and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising strategy for cancer therapy. Proteasome inhibitors induce the expression of death receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechanism of DR5 up-regulation has not been elucidated. In this study, we report that CCAAT/enhancer-binding protein homologous protein (CHOP) is a regulator of DR5 induction by proteasome inhibitor MG132. MG132 induced DR5 expression at a protein and mRNA level in prostate cancer DU145 cells. Furthermore, MG132 increased DR5 promoter activity. Using a series of deletion mutant plasmids containing DR5 promoters of various sizes, we found that MG132 stimulated the promoter activity via the region of −289 to −253. This region contained a CHOP-binding site. Site-directed mutation of the site abrogated the promoter activity enhanced by MG132. An electrophoretic mobility shift assay showed that CHOP directly bound to the MG132-responsive site on the DR5 promoter. Expression of the CHOP protein was increased with MG132 along with DR5 up-regulation. Furthermore, CHOP small interfering RNA attenuated the DR5 up-regulation due to MG132. These results indicate that the proteasome inhibitor MG132 induces DR5 expression through CHOP up-regulation.
8-Oxoguanine Formation Induced by Chronic UVB Exposure Makes Ogg1 Knockout Mice Susceptible to Skin Carcinogenesis
Authors: Kunisada Makoto , Sakumi Kunihiko , Tominaga Yohei , Budiyanto Arief , Ueda Masato , Ichihashi Masamitsu , Nakabeppu Yusaku , Nishigori Chikako 
Published: September 2005

Abstract
8-Oxoguanine is one of the oxidative DNA damages that can result in stable mutations. The Ogg1 gene encodes the repair enzyme 8-oxoguanine-DNA glycosylase, which removes the oxidized base from DNA. In this study, we investigated the role of 8-oxoguanine in skin carcinogenesis induced by UVB irradiation using Ogg1 knockout mice (C57Bl/6J background). We examined the effect of UVB irradiation on the formation of 8-oxoguanine in epidermal cells using immunostaining and found that the level of 8-oxoguanine in Ogg1 knockout mice 24 hours after UVB irradiation remained high compared with that in wild-type and heterozygous mice. To verify the effect of chronic UVB irradiation on 8-oxoguanine formations in epidermal cells, we irradiated wild-type, heterozygous, and Ogg1 knockout mice with UVB at a dose of 2.5 kJ/m2 thrice a week for 40 weeks. We found that the mean number of tumors in Ogg1 knockout mice was 3.71, which was significantly more than in wild-type and heterozygous mice, being 1.71 and 2.28, respectively. The rate of developing malignant tumors in Ogg1 knockout mice was also significantly higher (88.5%; squamous cell carcinomas, 73.1%; sarcomas, 15.4%) than in wild-type mice (50.0%; squamous cell carcinomas, 41.7%; sarcomas, 8.3%). Moreover, the age of onset of developing skin tumors in Ogg1 knockout mice was earlier than in the other types of mice. These results clearly indicate that oxidative DNA damage induced by sunlight plays an important role in the development of skin cancers.
Nestin-Linked Green Fluorescent Protein Transgenic Nude Mouse for Imaging Human Tumor Angiogenesis
Authors: Amoh Yasuyuki , Yang Meng , Li Lingna , Reynoso Jose , Bouvet Michael , Moossa Abdool R. , Katsuoka Kensei , Hoffman Robert M. 
Published: September 2005

Abstract
We report here a novel transgenic nude mouse for the visualization of human tumor angiogenesis. We have recently shown that the neural stem cell marker nestin is expressed in hair follicle stem cells and blood vessel networks in the skin of C57/B6 transgenic mice with nestin regulatory element–driven green fluorescent protein (ND-GFP). Others have shown ND-GFP is expressed in the brain, pancreas, and testes in these mice. In the present study, the nestin ND-GFP gene was crossed into nude mice on the C57/B6 background to obtain ND-GFP nude mice. ND-GFP was expressed in the brain, spinal cord, pancreas, stomach, esophagus, heart, lung, blood vessels of glomeruli, blood vessels of skeletal muscle, testes, hair follicles, and blood vessel network in the skin of ND-GFP nude mice. Human lung cancer, pancreatic cancer, and colon cancer cell lines as well as a murine melanoma cell line and breast cancer tumor cell line expressing red fluorescent protein were implanted orthotopically, and a red fluorescent protein–expressing human fibrosarcoma was implanted s.c. in the ND-GFP nude mice. These tumors grew extensively in the ND-GFP mice. ND-GFP was highly expressed in proliferating endothelial cells and nascent blood vessels in the growing tumors, visualized by dual-color fluorescence imaging. Results of immunohistochemical staining showed that CD31 was expressed in the ND-GFP–expressing nascent blood vessels. The ND-GFP transgenic nude mouse model enables the visualization of nascent angiogenesis in human and mouse tumor progression. These results suggest that this model is useful for the imaging of the angiogenesis of human as well as rodent tumors and visualization of the efficacy of angiogenetic inhibitors.
Human LATS1 Is a Mitotic Exit Network Kinase
Authors: Bothos John , Tuttle Robyn L. , Ottey Michelle , Luca Francis C. , Halazonetis Thanos D. 
Published: September 2005

Abstract
The kinase LATS/WARTS is a tumor suppressor protein conserved in evolution, but its function at the molecular level is not well understood. We report here that human LATS1 interacts with MOB1A, a protein whose homologue in budding yeast associates with kinases involved in mitotic exit. This suggested that LATS1 may be a component of the previously uncharacterized mitotic exit network in higher eukaryotes. Indeed, moderate overexpression of human LATS1 in cells exposed to microtubule poisons facilitated mitotic exit, and this activity required MOB1A. Reciprocally, small interfering RNA–mediated suppression of LATS1 or MOB1A prolonged telophase, but had no effect on the length of the earlier phases of mitosis. A role of LATS1 in mitotic exit may explain its previously described abilities to induce G2 arrest and promote cytokinesis.
Intrapulmonary IFN-β Gene Therapy Using an Adenoviral Vector Is Highly Effective in a Murine Orthotopic Model of Bronchogenic Adenocarcinoma of the Lung
Authors: Wilderman Michael J. , Sun Jing , Jassar Arminder S. , Kapoor Veena , Khan Mohamed , Vachani Anil , Suzuki Eiji , Kinniry Paul A. , Sterman Daniel H. , Kaiser Larry R. , Albelda Steven M. 
Published: September 2005

AbstractGiven previous work showing that an adenoviral vector expressing IFN-β (Ad.IFNβ) was highly effective in eradicating i.p. mesothelioma tumors, the antitumor efficacy of this agent was evaluated in an orthotopic model of bronchogenic adenocarcinoma of the lung. These transgenic mice have a conditionally expressed, oncogenic K-rasG12D allele that can be activated by intratracheal administration of an adenovirus expressing Cre recombinase (Ad.Cre). K-rasG12D mutant mice were given Ad.Cre intranasally to activate the oncogene. Mice were then given 109 plaque-forming units of a control vector (Ad.LacZ) or Ad.IFNβ intranasally 3 and 4 weeks later, a time when lung tumors had been established. Cells derived from K-ras-mutated lung tumors were also grown in the flanks of mice to study mechanisms of therapeutic responses. In two separate experiments, untreated tumor-bearing mice all died by day 57 (median survival, 49 days). Ad.LacZ-treated mice all died by day 71 (median survival, 65 days). In contrast, 90% to 100% of mice treated with Ad.IFNβ were long-term survivors (&gt;120 days; P &lt; 0.001). In addition, immunity to re-challenge with tumor cells was induced. In vitro and flank tumor studies showed that Ad.IFNβ induced direct tumor cell killing and that depleting natural killer or CD8+ T cells, but not CD4+ T cells, with antibodies attenuated the effect of Ad.IFNβ. These studies, showing remarkable antitumor activity in this orthotopic lung cancer model, provide strong preclinical support for a trial of Ad.IFNβ to treat human non–small cell lung cancer.
Kinase-Inactive Glycogen Synthase Kinase 3β Promotes Wnt Signaling and Mammary Tumorigenesis
Authors: Farago Marganit , Dominguez Isabel , Landesman-Bollag Esther , Xu Xin , Rosner Andrea , Cardiff Robert D. , Seldin David C. 
Published: September 2005

Abstract
Recent studies have implicated ectopic activation of the Wnt pathway in many human cancers, including breast cancer. β-catenin is a critical coactivator in this signaling pathway and is regulated in a complex fashion by phosphorylation, degradation, and nuclear translocation. Glycogen synthase kinase 3β (GSK3β) phosphorylation of the NH2-terminal domain of β-catenin targets it for ubiquitination and proteosomal degradation. We hypothesized that expression of kinase-inactive GSK3β (KI-GSK3β) in mammary glands would function in a dominant-negative fashion by antagonizing the endogenous activity of GSK3β and promoting breast cancer development. Consistent with this, we find that KI-GSK3β stabilizes β-catenin expression, catalyzes its localization to the nucleus, and up-regulates the downstream target gene, cyclin D1, in vitro. In vivo, transgenic mice overexpressing the KI-GSK3β under the control of the mouse mammary tumor virus-long terminal repeat develop mammary tumors with overexpression of β-catenin and cyclin D1. Thus, antagonism of GSK3β activity is oncogenic in the mammary epithelium; mutation or pharmacologic down-regulation of GSK3β could promote mammary tumors.
Therapeutic Index by Combination of Adriamycin and Docetaxel Depends on Dosing Time in Mice
Authors: Tabuchi Mayumi , To Hideto , Sakaguchi Hiromi , Goto Naho , Takeuchi Ayako , Higuchi Shun , Ohdo Shigehiro 
Published: September 2005

Abstract
Although the combination of adriamycin and docetaxel showed a better cure rate against metastatic breast cancer, severe myelosuppression and cardiotoxicity were dose-limiting factors. The purpose of this study was to establish a suitable dosing schedule, based on a chronopharmacologic approach, to relieve severe adverse effects. In experiment 1, adriamycin or docetaxel was injected i.p. at 2, 6, 10, 14, 18, or 22 hours after light onset (HALO) to estimate toxicities. In experiment 2, the dosing time dependency of toxicity and pharmacokinetics were assessed in the combination of adriamycin and docetaxel. In addition, G2-M phase in myelocyte cells was determined in nontreated mice. Adverse effects caused by adriamycin were shown to be the worst at 2 HALO and the best at 14 HALO. On the other hand, docetaxel-induced adverse effects were more severe at 14 HALO than at 2 HALO. In the combination study, the D(2)-A(14) group, in which docetaxel was administered at 2 HALO followed by adriamycin at 14 HALO, showed the most toxicity relief of all the treated groups. In the pharmacokinetic study, the dosing time dependency of toxicities was not related to the daily variation of pharmacokinetics of adriamycin and docetaxel. A significant 24-hour rhythm of G2-M phase distribution was found in myelocyte cells of nontreated mice. The daily variation of leukopenia caused by docetaxel corresponded to the 24-hour rhythm of G2-M phase distribution. These findings reveal that the therapeutic index of the combined chemotherapy can be improved by administering adriamycin and docetaxel at the time when the most adverse effects are relieved in each drug.
Tumor Dormancy and MYC Inactivation: Pushing Cancer to the Brink of Normalcy
Authors: Shachaf Catherine M. , Felsher Dean W. 
Published: September 2005

AbstractUpon MYC inactivation, tumors variously undergo proliferative arrest, cellular differentiation, and apoptosis and in some cases, apparently permanently revoking tumorigenesis. In liver tumor cells, we recently showed that MYC inactivation uncovers stem cell properties and triggers differentiation, but in this case, their neoplastic properties are restorable by MYC reactivation. Thus, whereas oncogene inactivation can push cancer to the brink of normalcy, some cells retain the latent capacity to turn cancerous again, arguing that they may exist in a state of tumor dormancy.
Identification of a Novel Prostate Tumor Target, Mindin/RG-1, for Antibody-Based Radiotherapy of Prostate Cancer
Authors: Parry Renate , Schneider Doug , Hudson Debra , Parkes Debbie , Xuan Jian-Ai , Newton Alicia , Toy Pam , Lin Rick , Harkins Rick , Alicke Bruno , Biroc Sandra , Kretschmer Peter J. , Halks-Miller Meredith , Klocker Helmut , Zhu Ying , Larsen Brent , Cobb Ronald R. , Bringmann Peter , Roth Georg , Lewis Jason S. , Dinter Harald , Parry Gordon 
Published: September 2005

Abstract
Gene expression analysis showed that a human mindin homologue, mindin/RG-1, is expressed selectively in prostate tissues and that its expression level is elevated in some prostate tumors. Mindin/RG-1 protein expression is maintained in &gt;80% of prostate cancers metastatic to bone or lymph nodes as well as in locally recurrent tumors in androgen-unresponsive patients. In contrast, mindin/RG-1 expression in other normal tissues is significantly lower than that seen in the prostate. A fully human antibody, 19G9, was generated against mindin/RG-1 protein and was shown to accumulate at high abundance in LNCaP tumor xenografts. Conjugates of this antibody with the chelator CHX-A″-DTPA were generated and radiolabeled with either 111In, 90Y, or 86Y. Small animal positron emission tomography imaging with the 86Y-radiolabeled conjugate showed very specific accumulation of the antibody in LNCaP tumor xenografts with clear tumor delineation apparent at 4 hours. The therapeutic efficacy of [90Y]-CHX-A″-DTPA-19G9 was evaluated in mice bearing LNCaP xenografts. A dose-finding study identified a nontoxic therapeutic dose to be ∼75 μCi. Significant antitumor effects were seen with a single administration of radiolabeled antibody to animals bearing 200 to 400 mm3 tumors. Inhibition of tumor growth was observed in all treated animals over a 49-day period. At 49 days posttreatment, slow tumor growth recurred but this could be prevented for an additional 40-day period by a second administration of a 75 μCi dose at day 49. We conclude that [90Y]-CHX-A″-DTPA-19G9 is a novel antibody conjugate that has considerable promise for therapy of metastatic prostate cancer in androgen-unresponsive patients.
Immortal ALT+ Human Cells Do Not Require Telomerase Reverse Transcriptase for Malignant Transformation
Authors: Sun Beicheng , Chen Meizhen , Hawks Christina L. , Hornsby Peter J. 
Published: September 2005

Abstract
Many human cancer cells lack telomerase activity but nevertheless maintain telomeres via a process termed “alternative lengthening of telomeres” (ALT). Despite being immortal and having a telomere maintenance mechanism, ALT+ human fibroblasts require telomerase reverse transcriptase (hTERT) for tumor formation in immunodeficient mice when tested by s.c. injection. Here we show that three ALT+ human SV40-immortalized fibroblast cell lines require only oncogenic RasV12G to be converted to a fully tumorigenic state. When cells were implanted beneath the kidney capsule of immunodeficient mice, they invaded the kidney and neighboring organs and metastasized to the lungs. RasV12G-expressing ALT+ cells remained completely telomerase negative. Introduction of hTERT conferred strong telomerase activity but did not appreciably change the malignant properties of the cells. However, when cells were tested by s.c. injection, RasV12G-transduced ALT+ cells did not form tumors, and in this site, hTERT was required for tumorigenicity. These data show that when the s.c. injection method is used as an assay for tumorigenicity, hTERT may be artifactually scored as an oncogene; the subrenal capsule assay shows that ALT, as a telomere maintenance mechanism, is equivalent to hTERT in neoplastic transformation of human cells by oncogenes.
Control of Genomic Instability and Epithelial Tumor Development by the p53-Fbxw7/Cdc4 Pathway
Authors: Perez-Losada Jesus , Mao Jian-Hua , Balmain Allan 
Published: September 2005

Abstract
Mouse models of cancer have provided novel insights into the timing of p53 loss during tumorigenesis. We have recently identified Fbxw7/Cdc4 as a downstream target of p53 loss that controls genomic instability and tumor development in epithelial tumors. Although p53-deficient mice primarily develop lymphomas and sarcomas, the additional loss of one copy of the Fbxw7 gene drives tumor development in a range of epithelial tissues. These data highlight the importance of genetic instability at the chromosome level in the development of common cancer types, and further illustrate the value of mouse models in identifying causal genetic events in epithelial tumor formation.