bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Primed Ebolavirus Glycoprotein (19-Kilodalton GP
1,2
): Sequence and Residues Critical for Host Cell Binding
Authors: Dube Derek , Brecher Matthew B. , Delos Sue E. , Rose Sean C. , Park Edward W. , Schornberg Kathryn L. , Kuhn Jens H. , White Judith M. 
Published: January 2009

ABSTRACT

Entry of ebolavirus (EBOV) into cells is mediated by its glycoprotein (GP
1,2
), a class I fusion protein whose structure was recently determined (J. E. Lee et al., Nature
454:
177-182, 2008). Here we confirmed two major predictions of the structural analysis, namely, the residues in GP
1
and GP
2
that remain after GP
1,2
is proteolytically primed by endosomal cathepsins for fusion and residues in GP
1
that are critical for binding to host cells. Mass spectroscopic analysis indicated that primed GP
1,2
contains residues 33 to 190 of GP
1
and all residues of GP
2
. The location of the receptor binding site was determined by a two-pronged approach. We identified a small receptor binding region (RBR), residues 90 to 149 of GP
1
, by comparing the cell binding abilities of four RBR proteins produced in high yield. We characterized the binding properties of the optimal RBR (containing GP
1
residues 57 to 149) and then conducted a mutational analysis to identify critical binding residues. Substitutions at four lysines (K95, K114, K115, and K140) decreased binding and the ability of RBR proteins to inhibit GP
1,2
-mediated infection. K114, K115, and K140 lie in a small region modeled to be located on the top surface of the chalice following proteolytic priming; K95 lies deeper in the chalice bowl. Combined with those of Lee et al., our findings provide structural insight into how GP
1,2
is primed for fusion and define the core of the EBOV RBR (residues 90 to 149 of GP
1
) as a highly conserved region containing a two-stranded β-sheet, the two intra-GP
1
disulfide bonds, and four critical Lys residues.
A Susceptibility Locus for Papillary Thyroid Carcinoma on Chromosome 8q24
Authors: He Huiling , Nagy Rebecca , Liyanarachchi Sandya , Jiao Hong , Li Wei , Suster Saul , Kere Juha , de la Chapelle Albert 
Published: January 2009

Abstract
Papillary thyroid carcinoma (PTC) displays higher heritability than most other cancers. To search for genes predisposing to PTC, we performed a genome-wide linkage analysis in a large family with PTC and melanoma. Among several peaks the highest was at 8q24, with a maximum nonparametric linkage (NPL) score of 7.03. Linkage analysis was then broadened to comprise 25 additional PTC families that produced a maximum NPL score of 3.2, P = 0.007 at the 8q24 locus. Fine mapping with microsatellite markers was compatible with linkage to the 8q24 locus in 10 of the 26 families. In the large family, a ∼320 Kb haplotype was shared by individuals with PTC, melanoma, or benign thyroid disease, but not by unaffected individuals. A 12 Kb haplotype of 8 SNP markers within the larger haplotype was shared by 9 of the 10 families in which the 8q24 locus was compatible with linkage. The shared haplotype is located within 2 known overlapping protein-coding genes, thyroglobulin (TG) and Src-like adaptor (SLA). Resequencing of the coding and control regions of TG and SLA did not disclose putative mutations in PTC patients. Embedded in the TG-SLA region are three likely noncoding RNA genes, one of which (AK023948) harbors the 8-SNP haplotype. Resequencing of AK023948 and one of the other RNA genes did not reveal candidate mutations. Gene expression analysis indicated that AK023948 is significantly down-regulated in most PTC tumors. The putative noncoding RNA gene AK023948 is a candidate suseptibility gene for PTC. [Cancer Res 2009;69(2):625–31]
Pancreatic Cancer and Precursor Pancreatic Intraepithelial Neoplasia Lesions Are Devoid of Primary Cilia
Authors: Seeley E. Scott , Carrière Catherine , Goetze Tobias , Longnecker Daniel S. , Korc Murray 
Published: January 2009

Abstract
Primary cilia have been proposed to participate in the modulation of growth factor signaling pathways. In this study, we determined that ciliogenesis is suppressed in both pancreatic cancer cells and pancreatic intraepithelial neoplasia (PanIN) lesions in human pancreatic ductal adenocarcinoma (PDAC). Primary cilia were absent in these cells even when not actively proliferating. Cilia were also absent from mouse PanIN cells in three different mouse models of PDAC driven by an endogenous oncogenic Kras allele. Inhibition of Kras effector pathways restored ciliogenesis in a mouse pancreatic cancer cell line, raising the possibility that ciliogenesis may be actively repressed by oncogenic Kras. By contrast, normal duct, islet, and centroacinar cells retained primary cilia in both human and mouse pancreata. Thus, arrested ciliogenesis is a cardinal feature of PDAC and its precursor PanIN lesions, does not require ongoing proliferation, and could potentially be targeted pharmacologically. [Cancer Res 2009;69(2):422–30]
De novo Induction of Genetically Engineered Brain Tumors in Mice Using Plasmid DNA
Authors: Wiesner Stephen M. , Decker Stacy A. , Larson Jon D. , Ericson Katya , Forster Colleen , Gallardo Jose L. , Long Chunmei , Demorest Zachary L. , Zamora Edward A. , Low Walter C. , SantaCruz Karen , Largaespada David A. , Ohlfest John R. 
Published: January 2009

Abstract
Spontaneous mouse models of cancer show promise to more accurately recapitulate human disease and predict clinical efficacy. Transgenic mice or viral vectors have been required to generate spontaneous models of glioma, a lethal brain tumor, because nonviral gene transfer is typically transient. To overcome this constraint, we used the Sleeping Beauty transposable element to achieve chromosomal integration of human oncogenes into endogenous brain cells of immunocompetent mice. Genetically engineered, spontaneous brain tumors were induced with plasmid DNA in a matter of weeks in three separate mouse strains. The phenotype of tumors was influenced by the combination of oncogenes delivered, resembling human astrocytoma or glioblastoma in the majority of cases. At least five different genes can be cotransfected simultaneously including reporters, allowing measurement of tumor viability by in vivo imaging. This model can accelerate brain tumor research in a variety of ways such as generation of “humanized” models for high throughput drug screening and candidate gene validation with exceptional speed and flexibility. [Cancer Res 2009;69(2):431–9]
p18Ink4c and p53 Act as Tumor Suppressors in Cyclin D1–Driven Primitive Neuroectodermal Tumor
Authors: Saab Raya , Rodriguez-Galindo Carlos , Matmati Kelly , Rehg Jerold E. , Baumer Shannon H. , Khoury Joseph D. , Billups Catherine , Neale Geoffrey , Helton Kathleen J. , Skapek Stephen X. 
Published: January 2009

Abstract
The retinoblastoma (RB) tumor suppressor pathway is likely important in primitive neuroectodermal tumors (PNET) of the brain. In fact, 10% to 15% of children born with RB mutations develop brain PNETs, commonly in the pineal gland. Cyclin D1, which in association with cyclin-dependent kinase (Cdk) 4 and Cdk6 phosphorylates and inactivates the RB protein, is expressed in 40% of sporadic medulloblastoma, a PNET of the cerebellum. To understand tumorigenic events cooperating with RB pathway disruption in brain PNET, we generated a transgenic mouse where cyclin D1 was expressed in pineal cells. Cyclin D1 enhanced pinealocyte proliferation, causing pineal gland enlargement. However, proliferation ceased beyond 2 weeks of age with reversal of Cdk4-mediated Rb phosphorylation despite continued expression of the transgene, and the pineal cells showed heterochromatin foci suggestive of a senescent-like state. In the absence of the p53 tumor suppressor, cell proliferation continued, resulting in pineal PNET that limited mouse survival to ∼4 months. Interestingly, the Cdk inhibitor p18Ink4c was induced in the transgenic pineal glands independently of p53, and transgenic mice that lacked Ink4c developed invasive PNET, although at an older age than those lacking p53. Analogous to our mouse model, we found that children with heritable RB often had asymptomatic pineal gland enlargement that only rarely progressed to PNET. Our finding that the Cdk4 inhibitor p18Ink4c is a tumor suppressor in cyclin D1–driven PNET suggests that pharmacologic interventions to inhibit Cdk4 activity may be a useful chemoprevention or therapeutic strategy in cancer driven by primary RB pathway disruption. [Cancer Res 2009;69(2):440–8]
Quantitative DNA Methylation Analysis of FOXP3 as a New Method for Counting Regulatory T Cells in Peripheral Blood and Solid Tissue
Authors: Wieczorek Georg , Asemissen Anne , Model Fabian , Turbachova Ivana , Floess Stefan , Liebenberg Volker , Baron Udo , Stauch Diana , Kotsch Katja , Pratschke Johann , Hamann Alf , Loddenkemper Christoph , Stein Harald , Volk Hans Dieter , Hoffmüller Ulrich , Grützkau Andreas , Mustea Alexander , Huehn Jochen , Scheibenbogen Carmen , Olek Sven 
Published: January 2009

Abstract
Regulatory T-cells (Treg) have been the focus of immunologic research due to their role in establishing tolerance for harmless antigens versus allowing immune responses against foes. Increased Treg frequencies measured by mRNA expression or protein synthesis of the Treg marker FOXP3 were found in various cancers, indicating that dysregulation of Treg levels contributes to tumor establishment. Furthermore, they constitute a key target of immunomodulatory therapies in cancer as well as transplantation settings. One core obstacle for understanding the role of Treg, thus far, is the inability of FOXP3 mRNA or protein detection methods to differentiate between Treg and activated T cells. These difficulties are aggravated by the technical demands of sample logistics and processing. Based on Treg-specific DNA demethylation within the FOXP3 locus, we present a novel method for monitoring Treg in human peripheral blood and solid tissues. We found that Treg numbers are significantly increased in the peripheral blood of patients with interleukin 2–treated melanoma and in formalin-fixed tissue from patients with lung and colon carcinomas. Conversely, we show that immunosuppressive therapy including therapeutic antibodies leads to a significant reduction of Treg from the peripheral blood of transplantation patients. In addition, Treg numbers are predictively elevated in the peripheral blood of patients with various solid tumors. Although our data generally correspond to data obtained with gene expression and protein-based methods, the results are less fluctuating and more specific to Treg. The assay presented here measures Treg robustly in blood and solid tissues regardless of conservation levels, promising fast screening of Treg in various clinical settings. [Cancer Res 2009;69(2):599–608]
Chromosomal Signatures of a Subset of High-Grade Premalignant Cervical Lesions Closely Resemble Invasive Carcinomas
Authors: Wilting Saskia M. , Steenbergen Renske D.M. , Tijssen Marianne , van Wieringen Wessel N. , Helmerhorst Theo J.M. , van Kemenade Folkert J. , Bleeker Maaike C.G. , van de Wiel Mark A. , Carvalho Beatriz , Meijer Gerrit A. , Ylstra Bauke , Meijer Chris J.L.M. , Snijders Peter J.F. 
Published: January 2009

Abstract
Cervical cancer develops from precancerous high-grade cervical intraepithelial neoplasia (CIN) harboring a transforming infection with high-risk human papillomavirus, which is characterized by p16INK4a overexpression. Once such a lesion has developed, progression toward an invasive squamous cell carcinoma (SCC) may take one or more decades, underlining the heterogeneity of these lesions in terms of duration of existence and progression risk. We performed array-based comparative genomic hybridization (array CGH) on 46 p16INK4a immunopositive CIN2/3 lesions to determine whether this heterogeneity is reflected in their chromosomal profiles. Chromosomal profiles of CIN2/3 lesions were related to those of invasive cervical SCC and promoter methylation of CADM1, a tumor suppressor gene known to be functionally involved in the tumorigenic phenotype of cervical cancer cells. Frequent alterations found in CIN2/3 lesions included gains located at chromosome 1, 3, 7, and 20 and losses located at 4, 11, 16, 17, and 19. Unsupervised hierarchical clustering identified two subsets of CIN2/3 lesions, chromosomal profiles of one of which closely resembled invasive SCCs. Gains of 1, 3q, and 20 were characteristic for CIN2/3 lesions with chromosomal signatures resembling carcinomas. In addition, dense promoter methylation of the CADM1 gene was significantly more frequent in these CIN2/3 lesions (P = 0.004). No chromosomal alterations were detected in six CIN1 lesions, five of which were completely p16INK4a immunonegative. These findings suggest that biomarkers associated with gains at chromosomes 1, 3q, and 20 are potential hallmarks of advanced p16INK4a-positive CIN2/3 lesions with a high short-term risk of progression. [Cancer Res 2009;69(2):647–55]
Tenascin-C Is a Novel RBPJκ-Induced Target Gene for Notch Signaling in Gliomas
Authors: Sivasankaran Balasubramanian , Degen Martin , Ghaffari Anthony , Hegi Monika E. , Hamou Marie-France , Ionescu Mihai-Constantin S. , Zweifel Christian , Tolnay Markus , Wasner Morten , Mergenthaler Susanne , Miserez André R. , Kiss Robert , Lino Maddalena M. , Merlo Adrian , Chiquet-Ehrismann Ruth , Boulay Jean-Louis 
Published: January 2009

Abstract
Tenascin-C (TNC) expression is known to correlate with malignancy in glioblastoma (GBM), a highly invasive and aggressive brain tumor that shows limited response to conventional therapies. In these malignant gliomas as well as in GBM cell lines, we found Notch2 protein to be strongly expressed. In a GBM tumor tissue microarray, RBPJk protein, a Notch2 cofactor for transcription, was found to be significantly coexpressed with TNC. We show that the TNC gene is transactivated by Notch2 in an RBPJk-dependent manner mediated by an RBPJk binding element in the TNC promoter. The transactivation is abrogated by a Notch2 mutation, which we detected in the glioma cell line Hs683 that does not express TNC. This L1711M mutation resides in the RAM domain, the site of interaction between Notch2 and RBPJk. In addition, transfection of constructs encoding activated Notch2 or Notch1 increased endogenous TNC expression identifying TNC as a novel Notch target gene. Overexpression of a dominant negative form of the transcriptional coactivator MAML1 or knocking down RBPJk in LN319 cells led to a dramatic decrease in TNC protein levels accompanied by a significant reduction of cell migration. Because addition of purified TNC stimulated glioma cell migration, this represents a mechanism for the invasive properties of glioma cells controlled by Notch signaling and defines a novel oncogenic pathway in gliomagenesis that may be targeted for therapeutic intervention in GBM patients. [Cancer Res 2009;69(2):458–65]
C-1027, A Radiomimetic Enediyne Anticancer Drug, Preferentially Targets Hypoxic Cells
Authors: Beerman Terry A. , Gawron Loretta S. , Shin Seulkih , Shen Ben , McHugh Mary M. 
Published: January 2009

Abstract
The hypoxic nature of cells within solid tumors limits the efficacy of anticancer therapies such as ionizing radiation and conventional radiomimetics because their mechanisms require oxygen to induce lethal DNA breaks. For example, the conventional radiomimetic enediyne neocarzinostatin is 4-fold less cytotoxic to cells maintained in low oxygen (hypoxic) compared with normoxic conditions. By contrast, the enediyne C-1027 was nearly 3-fold more cytotoxic to hypoxic than to normoxic cells. Like other radiomimetics, C-1027 induced DNA breaks to a lesser extent in cell-free, or cellular hypoxic, compared with normoxic environments. However, the unique DNA interstrand cross-linking ability of C-1027 was markedly enhanced under the same hypoxic conditions that reduced its DNA break induction. Although the unique chemistry of C-1027 allows it to concurrently generate both DNA breaks and cross-links in normoxic cells, a low oxygen environment represses the former and promotes the latter. Thus, treatment with C-1027 offers a facile approach for overcoming the radioresistance associated with poorly oxygenated cells. [Cancer Res 2009;69(2):OF593–6]
Overexpression of RhoA Induces Preneoplastic Transformation of Primary Mammary Epithelial Cells
Authors: Zhao Xiangshan , Lu Lin , Pokhriyal Nidhi , Ma Hui , Duan Lei , Lin Simon , Jafari Nadereh , Band Hamid , Band Vimla 
Published: January 2009

Abstract
Rho family small GTPases serve as molecular switches in the regulation of diverse cellular functions, including actin cytoskeleton remodeling, cell migration, gene transcription, and cell proliferation. Importantly, Rho overexpression is frequently seen in many carcinomas. However, published studies have almost invariably used immortal or tumorigenic cell lines to study Rho GTPase functions and there are no studies on the potential of Rho small GTPase to overcome senescence checkpoints and induce preneoplastic transformation of human mammary epithelial cells (hMEC). We show here that ectopic expression of wild-type (WT) RhoA as well as a constitutively active RhoA mutant (G14V) in two independent primary hMEC strains led to their immortalization and preneoplastic transformation. These cells have continued to grow over 300 population doublings (PD) with no signs of senescence, whereas cells expressing the vector or dominant-negative RhoA mutant (T19N) senesced after 20 PDs. Significantly, RhoA-T37A mutant, known to be incapable of interacting with many well-known Rho effectors including Rho kinase, PKN, mDia1, and mDia2, was also capable of immortalizing hMECs. Notably, similar to parental normal cells, Rho-immortalized cells have WT p53 and intact G1 cell cycle arrest on Adriamycin treatment. Rho-immortalized cells were anchorage dependent and were unable to form tumors when implanted in nude mice. Lastly, microarray expression profiling of Rho-immortalized versus parental cells showed altered expression of several genes previously implicated in immortalization and breast cancer progression. Taken together, these results show that RhoA can induce the preneoplastic transformation of hMECs by altering multiple pathways linked to cellular transformation and breast cancer. [Cancer Res 2009;69(2):483–91]
Apoptosis Repressor with Caspase Recruitment Domain Contributes to Chemotherapy Resistance by Abolishing Mitochondrial Fission Mediated by Dynamin-Related Protein-1
Authors: Wang Jian-Xun , Li Qian , Li Pei-Feng 
Published: January 2009

Abstract
One obstacle of cancer therapy is the development of cancer resistance to chemotherapy. The molecular mechanisms by which the resistance is developed remain to be fully understood. Apoptosis repressor with caspase recruitment domain (ARC) is an endogenous antiapoptotic protein. Here, we report that ARC contributes to chemotherapy resistance by abolishing mitochondrial fission mediated by dynamin-related protein-1 (Drp1). Our results show that both HeLa and human gastric cancer (SGC-7901) cells have a high expression level of ARC. Doxorubicin at a low dose can slightly induce apoptosis in HeLa and SGC-7901 cells. In contrast, knockdown of ARC by its RNA interference enables the same low dose of doxorubicin to significantly induce apoptosis in HeLa and SGC-7901 cells. These data indicate that ARC is responsible for the cell resistance to doxorubicin treatment. Mitochondrial fission has recently been shown to be involved in triggering apoptosis. In exploring the molecular mechanism by which ARC participates in antagonizing doxorubicin-induced apoptosis, we observed that doxorubicin is able to induce mitochondrial fission that can be inhibited by ARC. Our results further show that Drp1 accumulates in mitochondria and mediates the signal of doxorubicin to induce mitochondrial fission. ARC is able to prevent Drp1 accumulations in mitochondria. Finally, we identified that PUMA is required for Drp1 accumulations in mitochondria. ARC inhibits Drp1 accumulations in mitochondria by directly binding to PUMA. Taken together, our results reveal a chemotherapy-resistant model in which ARC inhibits PUMA-mediated Drp1 accumulations in mitochondria and the consequent mitochondrial fission. [Cancer Res 2009;69(2):492–500]
Targeting Ornithine Decarboxylase Impairs Development of MYCN-Amplified Neuroblastoma
Authors: Rounbehler Robert J. , Li Weimin , Hall Mark A. , Yang Chunying , Fallahi Mohammad , Cleveland John L. 
Published: January 2009

Abstract
Neuroblastoma is a pediatric malignancy that arises from the neural crest, and patients with high-risk neuroblastoma, which typically harbor amplifications of MYCN, have an extremely poor prognosis. The tyrosine hydroxylase (TH) promoter-driven TH-MYCN transgenic mouse model faithfully recapitulates many hallmarks of human MYCN-amplified neuroblastoma. A key downstream target of Myc oncoproteins in tumorigenesis is ornithine decarboxylase (Odc), the rate-limiting enzyme of polyamine biosynthesis. Indeed, sustained treatment with the Odc suicide inhibitor α-difluoromethylornithine (DFMO) or Odc heterozygosity markedly impairs lymphoma development in Eμ-Myc transgenic mice, and these effects are linked to the induction of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1, which is normally repressed by Myc. Here, we report that DFMO treatment, but not Odc heterozygosity, impairs MYCN-induced neuroblastoma and that, in this malignancy, transient DFMO treatment is sufficient to confer protection. The selective anticancer effects of DFMO on mouse and human MYCN-amplified neuroblastoma also rely on its ability to disable the proliferative response of Myc, yet in this tumor context, DFMO targets the expression of the p21Cip1 Cdk inhibitor, which is also suppressed by Myc oncoproteins. These findings suggest that agents, such as DFMO, that target the polyamine pathway may show efficacy in high-risk, MYCN-amplified neuroblastoma. [Cancer Res 2009;15(4):547–53]
Basal Subtype and MAPK/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK Inhibition
Authors: Mirzoeva Olga K. , Das Debopriya , Heiser Laura M. , Bhattacharya Sanchita , Siwak Doris , Gendelman Rina , Bayani Nora , Wang Nicholas J. , Neve Richard M. , Guan Yinghui , Hu Zhi , Knight Zachary , Feiler Heidi S. , Gascard Philippe , Parvin Bahram , Spellman Paul T. , Shokat Kevan M. , Wyrobek Andrew J. , Bissell Mina J. , McCormick Frank , Kuo Wen-Lin , Mills Gordon B. , Gray Joe W. , Korn W. Michael 
Published: January 2009

Abstract
Specific inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) have been developed that efficiently inhibit the oncogenic RAF-MEK-ERK pathway. We used a systems-based approach to identify breast cancer subtypes particularly susceptible to MEK inhibitors and to understand molecular mechanisms conferring resistance to such compounds. Basal-type breast cancer cells were found to be particularly susceptible to growth inhibition by small-molecule MEK inhibitors. Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in response to MEK inhibition through a negative MEK-epidermal growth factor receptor-PI3K feedback loop was found to limit efficacy. Interruption of this feedback mechanism by targeting MEK and PI3K produced synergistic effects, including induction of apoptosis and, in some cell lines, cell cycle arrest and protection from apoptosis induced by proapoptotic agents. These findings enhance our understanding of the interconnectivity of oncogenic signal transduction circuits and have implications for the design of future clinical trials of MEK inhibitors in breast cancer by guiding patient selection and suggesting rational combination therapies. [Cancer Res 2009;69(2):565–72]