bluuebunny/crossref_metadata_2025_split huggingface dataset:
Calmodulin-Dependent Cyclic Nucleotide Phosphodiesterase (PDE1) Is a Pharmacological Target of Differentiation-Inducing Factor-1, an Antitumor Agent Isolated from
Dictyostelium
Authors: Shimizu Kasumi , Murata Taku , Tagawa Toshiro , Takahashi Katsunori , Ishikawa Ryoki , Abe Yumiko , Hosaka Kohei , Kubohara Yuzuru 
Published: September 2005

Abstract
The differentiation-inducing factor-1 (DIF-1) isolated from Dictyostelium discoideum is a potent antiproliferative agent that induces growth arrest and differentiation in mammalian cells in vitro. However, the specific target molecule(s) of DIF-1 has not been identified. In this study, we have tried to identify the target molecule(s) of DIF-1 in mammalian cells, examining the effects of DIF-1 and its analogs on the activity of some candidate enzymes. DIF-1 at 10–40 μm dose-dependently suppressed cell growth and increased the intracellular cyclic AMP concentration in K562 leukemia cells. It was then found that DIF-1 at 0.5–20 μm inhibited the calmodulin (CaM)-dependent cyclic nucleotide phosphodiesterase (PDE1) in vitro in a dose-dependent manner. Kinetic analysis revealed that DIF-1 acted as a competitive inhibitor of PDE1 versus the substrate cyclic AMP. Because DIF-1 did not significantly affect the activity of other PDEs or CaM-dependent enzymes and, in addition, an isomer of DIF-1 was a less potent inhibitor, we have concluded that PDE1 is a pharmacological and specific target of DIF-1.
Cure of Fisher Rats Bearing Radioresistant F98 Glioma Treated with
cis
-Platinum and Irradiated with Monochromatic Synchrotron X-Rays
Authors: Biston Marie-Claude , Joubert Aurélie , Adam Jean-François , Elleaume Hélène , Bohic Sylvain , Charvet Anne-Marie , Estève François , Foray Nicolas , Balosso Jacques 
Published: September 2005

Abstract
High-grade gliomas are usually of poor prognosis, and conventional radiotherapy, even combined with chemotherapy, still fails to improve the survival of patients. Here, we propose an innovative therapeutic approach combining synchrotron radiation with cis-diamminedichloroplatinum (II) (CDDP). As suggested previously, monochromatic synchrotron irradiation of CDDP at 78.8 keV, just above the 78.4 keV platinum absorption K-edge, leads to an enhanced photoelectric effect and an increased local toxicity. To select a particular radiation energy that could provide supra-additive effect, we used pulsed-field gel electrophoresis to assess yields of DNA double-strand breaks induced in rat F98 glioma cells after CDDP treatment combined with synchrotron X-rays. Thereafter, intracerebral CDDP injection combined with synchrotron X-rays was applied to Fisher rats bearing F98 glioma. CDDP concentrations were mapped by synchrotron X-ray microfluorescence. An extra number of more slowly repaired double strand breaks were observed when irradiating CDDP-treated F98 cells at 78.8 keV. In vivo treatments were then performed with different radiation doses and CDDP concentrations. All cell inoculations in rat brain resulted in tumor development, and tumor presence was controlled by computed tomography. Among all of the conditions tested, the combination of 3 μg of CDDP with 15 Gy resulted in the largest median survival time (206 days). After 1 year, about 34% of treated rats were still alive. This preclinical finding, validated by molecular analysis, represents the most protracted survival reported with this radioresistant glioma model and demonstrates the interest in powerful monochromatic X-ray sources as new tools for cancer treatments.
The RET Receptor Is Linked to Stress Response Pathways
Authors: Myers Shirley M. , Mulligan Lois M. 
Published: September 2005

Abstract
RET is a transmembrane receptor required for the development of neuroendocrine and urogenital cell types. Activation of RET has roles in cell growth, migration, or differentiation, yet little is known about the gene expression patterns through which these processes are mediated. We have generated cell lines stably expressing either the RET9 or RET51 protein isoforms and have used these to investigate RET-mediated gene expression patterns by cDNA microarray analyses. As seen for many oncogenes, we identified altered expression of genes associated generally with cell–cell or cell-substrate interactions and up-regulation of tumor-specific transcripts. We also saw increased expression of transcripts normally associated with neural crest or other RET-expressing cell types, suggesting these genes may lie downstream of RET activation in development. The most striking pattern of expression was up-regulation of stress response genes. We showed that RET expression significantly up-regulated the genes for heat shock protein (HSP) 70 family members, HSPA1A, HSPA1B, and HSPA1L. Other members of several HSP families and HSP70-interacting molecules that were associated with stress response protein complexes involved in protein maturation were also specifically up-regulated by RET, whereas those associated with the roles of HSP70 in protein degradation were down-regulated or unaffected. The major mechanism of stress response induction is activation of the heat shock transcription factor HSF1. We showed that RET expression leads to increased HSF1 activation, which correlates with increased expression of stress response genes. Together, our data suggest that RET may be directly responsible for expression of stress response proteins and the initiation of stress response.
Loss of Disialyl Lewisa, the Ligand for Lymphocyte Inhibitory Receptor Sialic Acid-Binding Immunoglobulin-Like Lectin-7 (Siglec-7) Associated with Increased Sialyl Lewisa Expression on Human Colon Cancers
Authors: Miyazaki Keiko , Ohmori Katsuyuki , Izawa Mineko , Koike Tetsufumi , Kumamoto Kensuke , Furukawa Koichi , Ando Takayuki , Kiso Makoto , Yamaji Toshiyuki , Hashimoto Yasuhiro , Suzuki Akemi , Yoshida Aruto , Takeuchi Makoto , Kannagi Reiji 
Published: September 2005

Abstract
Expression of sialyl Lewisa is known to be increased in cancers of the digestive organs. The determinant serves as a ligand for E-selectin and mediates hematogenous metastasis of cancers. In contrast, disialyl Lewisa, which has an extra sialic acid attached at the C6-position of penultimate GlcNAc in sialyl Lewisa, is expressed preferentially on nonmalignant colonic epithelial cells, and its expression decreases significantly on malignant transformation. Introduction of the gene for an α2→6 sialyl-transferase responsible for disialyl Lewisa synthesis to colon cancer cells resulted in a marked increase in disialyl Lewisa expression and corresponding decrease in sialyl Lewisa expression. This was accompanied by the complete loss of E-selectin binding activity of the cells. In contrast, the transfected cells acquired significant binding activity to sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7)/p75/adhesion inhibitory receptor molecule-1, an inhibitory receptor expressed on lymphoid cells. These results indicate that the transition of carbohydrate determinants from disialyl Lewisa-dominant status to sialyl Lewisa-dominant status on malignant transformation has a dual functional consequence: the loss of normal cell-cell recognition between mucosal epithelial cells and lymphoid cells on one hand and the gain of E-selectin binding activity on the other. The transcription of a gene encoding the α2→6 sialyltransferase was markedly down-regulated in cancer cells compared with nonmalignant epithelial cells, which is in line with the decreased expression of disialyl Lewisa and increased expression of sialyl Lewisa in cancers. Treatment of cancer cells with butyrate or 5-azacytidine induced strongly disialyl Lewisa expression, suggesting that histone deacetylation and/or DNA methylation may be involved in the silencing of the gene in cancers.
Gene Expression in the Urinary Bladder
Authors: Dyrskjøt Lars , Kruhøffer Mogens , Thykjaer Thomas , Marcussen Niels , Jensen Jens L. , Møller Klaus , Ørntoft Torben F. 
Published: September 2005

Abstract
The presence of carcinoma in situ (CIS) lesions in the urinary bladder is associated with a high risk of disease progression to a muscle invasive stage. In this study, we used microarray expression profiling to examine the gene expression patterns in superficial transitional cell carcinoma (sTCC) with surrounding CIS (13 patients), without surrounding CIS lesions (15 patients), and in muscle invasive carcinomas (mTCC; 13 patients). Hierarchical cluster analysis separated the sTCC samples according to the presence or absence of CIS in the surrounding urothelium. We identified a few gene clusters that contained genes with similar expression levels in transitional cell carcinoma (TCC) with surrounding CIS and invasive TCC. However, no close relationship between TCC with adjacent CIS and invasive TCC was observed using hierarchical cluster analysis. Expression profiling of a series of biopsies from normal urothelium and urothelium with CIS lesions from the same urinary bladder revealed that the gene expression found in sTCC with surrounding CIS is found also in CIS biopsies as well as in histologically normal samples adjacent to the CIS lesions. Furthermore, we also identified similar gene expression changes in mTCC samples. We used a supervised learning approach to build a 16-gene molecular CIS classifier. The classifier was able to classify sTCC samples according to the presence or absence of surrounding CIS with a high accuracy. This study demonstrates that a CIS gene expression signature is present not only in CIS biopsies but also in sTCC, mTCC, and, remarkably, in histologically normal urothelium from bladders with CIS. Identification of this expression signature could provide guidance for the selection of therapy and follow-up regimen in patients with early stage bladder cancer.
The
tyrp1
-Tag/
tyrp1
-FGFR1-DN Bigenic Mouse
Authors: Rousseau Benoı̂t , Larrieu-Lahargue Frédéric , Javerzat Sophie , Guilhem-Ducléon Frédéric , Beermann Friedrich , Bikfalvi Andreas 
Published: September 2005

Abstract
We describe herein a new transgenic mouse tumor model in which fibroblast growth factor (FGF) receptor activity is selectively inhibited. Tyrp1-Tag mice that develop early vascularized tumors of the retinal pigment epithelium were crossed with tyrp1-FGFR1-DN mice that express dominant-negative FGF receptors in the retinal pigment epithelium to generate bigenic mice. Initial angiogenesis-independent tumor growth progressed equally in tyrp1-Tag and bigenic mice with no significant differences in the number of dividing and apoptotic cells within the tumor. By contrast, at a later stage when tyrp1-Tag tumors rapidly expanded to fill the entire eye posterior chamber and migrate along the optic nerve toward the chiasma, bigenic tumors remained small and were poorly vascularized. Secondary tumors of small size developed in only 20% of bigenic mice by 1 month. Immunohistochemical analysis of secondary tumors from bigenic mice showed a reduction of angiogenesis and an increase in apoptosis in tumor cells. Tumor cells from bigenic mice expressed high levels of truncated FGF receptors and did not induce endothelial tube formation in vitro. All in all, this indicates that the tyrp1-Tag mouse may be a useful model to study selective tumor inhibition and the effect of antitumor therapy that targets a specific growth factor pathway. FGF receptors are required at the onset of tumor invasion and angiogenesis in ocular tumors and are good therapeutic targets in this model. The bigenic mouse may also constitute a useful model to answer more fundamental questions of cancer biology such as the mechanism of tumor escape.
Comparison of the Effect of Mutant and Wild-Type p53 on Global Gene Expression
Authors: O’Farrell Thomas J. , Ghosh Paritosh , Dobashi Nobuaki , Sasaki Carl Y. , Longo Dan L. 
Published: September 2005

Abstract
The mechanisms for “gain-of-function” phenotypes produced by mutant p53s such as enhanced proliferation, resistance to transforming growth factor-β–mediated growth suppression, and increased tumorigenesis are not known. One theory is that these phenotypes are caused by novel transcriptional regulatory events acquired by mutant p53s. Another explanation is that these effects are a result of an imbalance of functions caused by the retention of some of the wild-type transcriptional regulatory events in the context of a loss of other counterbalancing activities. An analysis of the ability of DNA-binding domain mutants A138P and R175H, and wild-type p53 to regulate the expression levels of 6.9 × 103 genes revealed that the mutants retained only &lt;5% of the regulatory activities of the wild-type protein. A138P p53 exhibited mostly retained wild-type regulatory activities and few acquired novel events. However, R175H p53 possessed an approximately equal number of wild-type regulatory events and novel activities. This is the first report that, after examination of the regulation of a large unfocused set of genes, provides data indicating that remaining wild-type transcriptional regulatory functions existing in the absence of counterbalancing activities as well as acquired novel events both contribute to the gain-of-function phenotypes produced by mutant p53s. However, mutant p53s are likely to be distinct in terms of the extent to which each mechanism contributes to their gain-of-function phenotypes.
Orlistat Is a Novel Inhibitor of Fatty Acid Synthase with Antitumor Activity
Authors: Kridel Steven J. , Axelrod Fumiko , Rozenkrantz Natasha , Smith Jeffrey W. 
Published: September 2005

Abstract
One of the fundamental principles of pharmacology is that most drugs have side effects. Although considerable attention is paid to detrimental side effects, drugs can also have beneficial side effects. Given the time and expense of drug development, it would be particularly exciting if a systematic method could be applied to reveal all of the activities, including the unappreciated actions, of a potential drug. The present study takes the first step along this path. An activity-based proteomics strategy was used to simultaneously identify targets and screen for their inhibitors in prostate cancer. Orlistat, a Food and Drug Administration-approved drug used for treating obesity, was included in this screen. Surprisingly, we find a new molecular target and a potential new application for Orlistat. Orlistat is a novel inhibitor of the thioesterase domain of fatty acid synthase, an enzyme strongly linked to tumor progression. By virtue of its ability to inhibit fatty acid synthase, Orlistat halts tumor cell proliferation, induces tumor cell apoptosis, and inhibits the growth of PC-3 tumors in nude mice.
Bcl-2 Inhibitors Sensitize Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by Uncoupling of Mitochondrial Respiration in Human Leukemic CEM Cells
Authors: Hao Ji-Hui , Yu Ming , Liu Feng-Ting , Newland Adrian C. , Jia Li 
Published: September 2005

AbstractPrevious studies have shown that the lymphoblastic leukemia CEM cell line is resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis because of a low expression of caspase-8. Bcl-2 inhibitors, BH3I-2′ and HA14-1, are small cell-permeable nonpeptide compounds, are able to induce apoptosis by mediating cytochrome c release, and also lead to dissipation of the mitochondrial membrane potential (ΔΨm). This study aimed to use the Bcl-2 inhibitors to sensitize CEM cells to TRAIL-induced apoptosis by switching on the mitochondrial apoptotic pathway. We found that a low dose of BH3I-2′ or HA14-1, which did not induce cytochrome c release, greatly sensitized CEM cells to TRAIL-induced apoptosis. In a similar manner to the classical uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), both BH3I-2′ and HA14-1 induced a reduction in ΔΨm, a generation of reactive oxygen species (ROS), an increased mitochondrial respiration, and a decreased ATP synthesis. This uncoupling function of the Bcl-2 inhibitors was responsible for the synergy with TRAIL-induced apoptosis. CCCP per se did not induce apoptosis but again sensitized CEM cells to TRAIL-induced apoptosis by uncoupling mitochondrial respiration. The uncoupling effect facilitated TRAIL-induced Bax conformational change and cytochrome c release from mitochondria. Inhibition of caspases failed to block TRAIL-mediated cell death when mitochondrial respiration was uncoupled. We observed that BH3I-2′, HA14-1, or CCCP can overcome resistance to TRAIL-induced apoptosis in TRAIL-resistant cell lines, such as CEM, HL-60, and U937. Our results suggest that the uncoupling of mitochondrial respiration can sensitize leukemic cells to TRAIL-induced apoptosis. However, caspase activation per se does not represent an irreversible point of commitment to TRAIL-induced cell death when mitochondrial respiration is uncoupled.
γ Synuclein, a Novel Heat-Shock Protein-Associated Chaperone, Stimulates Ligand-Dependent Estrogen Receptor α Signaling and Mammary Tumorigenesis
Authors: Jiang Yangfu , Liu Yiliang Ellie , Goldberg Itzhak D. , Shi Y. Eric 
Published: September 2005

Abstract
Synucleins are emerging as central players in the formation of pathologically insoluble deposits characteristic of neurodegenerative diseases. γ synuclein (SNCG), previously identified as a breast cancer-specific gene (BCSG1), is also highly associated with breast or ovarian cancer progression. However, the molecular targets of SNCG aberrant expression in breast cancer have not been identified. Here, we demonstrated a chaperone activity of SNCG in the heat-shock protein (Hsp)-based multiprotein chaperone complex for stimulation of estrogen receptor (ER)-α signaling. As an ER-α-associated chaperone, SNCG participated in Hsp-ER-α complex, enhanced the high-affinity ligand-binding capacity of ER-α, and stimulated ligand-dependent activation of ER-α. The SNCG-mediated stimulation of ER-α transcriptional activity is consistent with its stimulation of mammary tumorigenesis in response to estrogen. These data indicate that SNCG is a new chaperone protein in the Hsp-based multiprotein chaperone complex for stimulation of ligand-dependent ER-α signaling and thus stimulates hormone-responsive mammary tumorigenesis.
The Phosphorylation of EphB2 Receptor Regulates Migration and Invasion of Human Glioma Cells
Authors: Nakada Mitsutoshi , Niska Jared A. , Miyamori Hisashi , McDonough Wendy S. , Wu Jie , Sato Hiroshi , Berens Michael E. 
Published: September 2005

Abstract
Eph receptor tyrosine kinases and their ligands, ephrins, mediate neurodevelopmental processes such as boundary formation, axon guidance, vasculogenesis, and cell migration. We determined the expression profiles of the Eph family members in five glioma cell lines under migrating and nonmigrating conditions. EphB2 mRNA was overexpressed in all five during migration (1.2–2.8-fold). We found abundant EphB2 protein as well as strong phosphorylation of EphB2 in migrating U87 cells. Confocal imaging showed EphB2 localized in lamellipodia of motile U87 cells. Treatment with ephrin-B1/Fc chimera stimulated migration and invasion of U87, whereas treatment with a blocking EphB2 antibody significantly inhibited migration and invasion. Forced expression of EphB2 in U251 cells stimulated cell migration and invasion and diminished adhesion concomitant with the tyrosine phosphorylation of EphB2. U251 stably transfected with EphB2 showed more scattered and more pronounced invasive growth in an ex vivo rat brain slice. In human brain tumor specimens, EphB2 expression was higher in glioblastomas than in low-grade astrocytomas or normal brain; patterns of phosphorylated EphB2 matched the expression levels. Laser capture microdissection of invading glioblastoma cells revealed elevated EphB2 mRNA (1.5–3.5-fold) in 7 of 7 biopsy specimens. Immunohistochemistry demonstrated EphB2 localization primarily in glioblastoma cells (56 of 62 cases) and not in normal brain. This is the first demonstration that migrating glioblastoma cells overexpress EphB2 in vitro and in vivo; glioma migration and invasion are promoted by activation of EphB2 or inhibited by blocking EphB2. Dysregulation of EphB2 expression or function may underlie glioma invasion.
Antiapoptotic Function of Apoptosis Inhibitor 2-MALT1 Fusion Protein Involved in t(11;18)(q21;q21) Mucosa-Associated Lymphoid Tissue Lymphoma
Authors: Hosokawa Yoshitaka , Suzuki Hiroko , Suzuki Yasuyuki , Takahashi Ryosuke , Seto Masao 
Published: September 2005

Abstract
t(11;18)(q21;q21) is a characteristic chromosomal translocation in mucosa-associated lymphoid tissue (MALT) type lymphoma, and this translocation results in fusion transcript of apoptosis inhibitor 2 (API2), also known as c-IAP2, and MALT translocation gene 1 (MALT1). Although the API2-MALT1 fusion protein has been shown to enforce activation of nuclear factor κB signaling, its precise role in the apoptotic signaling pathway remains to be established. To identify proteins that bind the API2-MALT1 protein, we used coimmunoprecipitation and SDS-PAGE, followed by liquid chromatography-electrospray ionization tandem mass spectrometry. As a result, three important regulators of apoptosis, Smac, HtrA2, and TRAF2, and three other proteins were identified as potential API2-MALT1-binding proteins. Immunoprecipitation analyses verified that API2-MALT1 indeed binds to both exogeneous and endogeneous Smac proteins. It is especially noteworthy that stably transfected API2-MALT1 significantly suppressed both UV- and etoposide-induced apoptosis in HeLa cells, thus demonstrating for the first time that API2-MALT1 indeed possesses antiapoptotic function. Furthermore, API2-MALT1 significantly suppressed Smac-promoted apoptosis in UV-irradiated HeLa cells. Thus, our results provide direct experimental evidence that API2-MALT1 can confer resistance to apoptosis, at least in part, by neutralizing apoptosis promoted by Smac.
Transcriptional Gene Silencing Promotes DNA Hypermethylation through a Sequential Change in Chromatin Modifications in Cancer Cells
Authors: Stirzaker Clare , Song Jenny Z. , Davidson Ben , Clark Susan J. 
Published: September 2005

Abstract
It is well established that DNA hypermethylation of tumor suppressor and tumor-related genes can occur in cancer cells and that each cancer subtype has specific gene sets that are commonly susceptible to methylation and silencing. Glutathione S-transferase (GSTP1) is one example of a gene that is hypermethylated and inactivated in the majority of prostate cancers. We previously reported that hypermethylation of the GSTP1 CpG island promoter in prostate cancer cells is initiated by a combination of transcriptional gene silencing (by removal of the Sp1 sites) and seeds of methylation that, instead of being constantly removed because of demethylation associated with transcription, acts as a catalyst for the spread of methylation across the CpG island. In this study, we now demonstrate that the seeds of DNA methylation also play an important role in initiating chromatin modification. Our results address a number of central questions about the temporal relationship between gene expression, DNA hypermethylation, and chromatin modification in cancer cells. We find that for the GSTP1 gene, (a) histone acetylation is independent of gene expression, (b) histone deacetylation is triggered by seeds of DNA methylation, (c) the spread of DNA hypermethylation across the island is linked to MBD2 and not MeCP2 binding, and (d) histone methylation occurs after histone deacetylation and is associated with extensive DNA methylation of the CpG island. These findings have important implications for understanding the biochemical events underlying the mechanisms responsible for abnormal hypermethylation of CpG island-associated genes in cancer cells.