bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 11: Asymmetric division via nonrandom chromosomal cosegregation potentially defines a novel class of universal cancer stem cells
Authors: Xin Hong-Wu , Hari Danielle M. , Jaiswal Kshama R. , Kim Bo-Kyu , Ray Satyajit , Koizumi Tomotake , Wiegand Gordon W. , Steinberg Seth M. , Garfield Susan H. , Andersen Jesper B. , Factor Valentina M. , Thorgeirsson Snorri S. , Avital Itzhak 
Published: February 2011

Abstract
Cancer stem cells (CSC) are thought to be responsible for cancer initiation, maintenance, and therapeutic failure. A hallmark of stem cells is self-renewal via asymmetric cell division (ACD) into daughter stem cells and cells predestined for differentiation. In addition, recent reports questioned the ability of the gold standard for testing CSC (xenotransplantation into immunodeficient mice) to truly detect and test CSC. The aim of this study was to demonstrate fundamental stem cell's traits such as ACD with non-random-chromosomal cosegregation (ACD-NRCC) in cancers.
Here, we show that a unique self-renewal mechanism i.e. ACD-NRCC occurs in various human cancers using DNA double labeling and confocal microscopy. ACD-NRCC was found exclusively in a subpopulation of CSC (side population and CD133+ cells) and not in the non-cancer-stem-cells fractions. Cells that demonstrated ACD-NRCC also exhibited superior tumor initiation capacity in nude mice (p=0.028). Furthermore, we found that the niche provided by the non-stem cancer cells directly regulates self-renewal via ACD-NRCC. This regulation is dependent on a potentially novel heat sensitive soluble factor (Self Renewal Factor, SRF). Gene expression microarray data showed down-regulation of genes associated with ACD in tested cancers.
Detection of ACD-NRCC in various human cancers provides direct evidence for the existence of cancer cells with unique stem cells traits. This is the first report to demonstrate the fundamental stem cells trait of ACD-NRCC in human cancer. Detection of cells capable of undergoing ACD-NRCC in various cancers potentially defines a novel class of CSC with superior tumor initiating capacity. Using ACD-NRCC, we propose a universal method for testing, isolating and targeting CSC. The gene expression microarray data suggested that faulty mechanisms of ACD-NRCC might result in stem cells derived cancers. Further purification of the niche's self-renewal-signals and utilizing our methodology for isolation of CSC have far reaching implications in regenerative medicine, cancer genetics and potential novel cancer therapeutics targeting CSC via ACD-NRCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 11.
Abstract 1102: Regulation of protein citrullination through p53/PADI4 network in DNA damage response
Authors: Matsuda Koichi , Tanikawa Chizu , Nakamura Yusuke 
Published: February 2011

Abstract
Upon wide range of cellular stresses, p53 is activated and inhibits malignant transformation through the transcriptional regulation of its target genes related to apoptosis, cell cycle arrest, and DNA repair. However its involvement in post-translational modifications of proteins has not been well characterized so far. We here report the novel role of p53 in the regulation of protein citrullination. Citrullination (also referred as deimination) is one form of PTMs converting an arginine residue in protein to a citrulline residue. This reaction is mediated by a Ca2+-dependent enzyme called as peptidylarginine deiminase. Citrullination of proteins results in a loss of positive charge and causes a significant biochemical change. On the other hand, citrullinated peptides/proteins are recognized as a non-self protein and subsequently activate immune systems. Hence, protein citrullination is now considered to play a pivotal role in various human diseases, but any roles of citrullination in carcinogenesis were not reported so far.
We found p53 transactivated peptidylarginine deiminase type 4 (PADI4) through intronic p53-binding site and ectopic expression of p53 or PADI4 induced protein citrullination. In addition, various proteins were citrullinated in response to DNA damage, but knockdown of PADI4 or p53 remarkably inhibited their citrullination, indicating the regulation of protein citrullination in a p53/PADI4 dependent manner. We identified that PADI4 citrullinated histone chaperon protein, nucleophosmin (NPM1) at arginine 197 residue in vivo under physiological condition. NPM1 was shown to continuously shuttle between the nucleus and cytoplasm and translocate from nucleoli to nucleoplasm as a response to DNA damage. Therefore, we investigated the effect of protein citrullination on subcellular localization of NPM1. Immunocytochemical analysis revealed that citrullination of NPM1 by PADI4 resulted in its translocation from nucleoli to nucleoplasm, while PADI4 did not alter the localization of mutant NPM1 (R197K). Furthermore, ectopic expression of PADI4 inhibited tumor cell growth, and concordantly knockdown of PADI4 attenuated p53-mediated growth inhibitory activity, demonstrating the significance of PADI4-mediated protein citrullination in the p53 signaling pathway.
Most of previous studies assessing enzymatic activities of PADIs were conducted under non-physiological condition using Ca ionophore or at higher Ca concentration. To our knowledge, this is the first report demonstrating the physiological regulatory mechanism of protein citrullination. Thus, p53 that can directly or indirectly modulate biological property of various proteins through the protein citrullination.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1102.
Abstract 1104: Perturbation of 60S ribosomal biogenesis results in ribosomal protein L5 and L11-dependent p53 activation
Authors: Sun Xiao-Xin , Dai Mushui 
Published: February 2011

Abstract
Ribosomal proteins play an important role in p53 activation in response to ribosomal stress. Multiple ribosomal proteins, including L5, L11, L23, and S7, have been shown to bind and inhibit MDM2, leading to p53 activation. However, it is not known whether ribosomal protein inhibition of MDM2 is specific to certain, but not all, ribosomal proteins. Here, we show that L29 and L30, two ribosomal proteins from the large ribosome subunit, do not bind to MDM2 and do not inhibit MDM2-mediated p53 suppression, indicating that the ribosomal protein regulation of the MDM2-p53 feedback loop is specific. Interestingly, direct perturbation of the 60S ribosomal biogenesis by knocking down either L29 or L30 drastically induced the level and activity of p53, leading to p53-depedent cell cycle arrest. Furthermore, this p53 activation requires ribosomal proteins L5 and L11, as knocking down either L5 or L11 completely abolished p53 activation induced by knockdown of L29 or L30. Consistently, knockdown of L29 or L30 enhances the interaction of MDM2 with L5 and L11. These results suggest that direct perturbation of the 60S ribosomal biogenesis activates p53 via L5 and L11-mediated MDM2 suppression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1104.
Abstract 1115: Epigenetic regulation of BRCA-1 by xenobiotic and dietary ligands of the aryl hydrocarbon receptor
Authors: Romagnolo Donato F. , Selmin Ornella I. , Papoutsis Andreas J. 
Published: February 2011

Abstract
Mutations of BRCA-1 account for only 5-10% of breast cancer cases, whereas sporadic breast tumors represent the remaining 90-95%. In sporadic breast cancers there is silencing of BRCA-1 in the absence of mutations. Factors contributing to this etiology may include environmental ligands of the aryl hydrocarbon receptor (AhR) such as dioxins (ex.2,3,7,8 tetrachlorodibenzene(p)dioxin, TCDD) and polycyclic aryl hydrocarbons (PAHs). Dietary ligands of the AhR with potential protective effects include the phytoalexin resveratrol found in grapes. In this study, we investigated the mechanisms responsible for repression of BRCA-1 expression by the activated AhR. The results of DNA binding studies in MCF-7 breast cancer cells documented that TCDD-induced the association of the AhR to xenobiotic responsive elements (XRE) harbored in the BRCA-1 promoter region. The cotreatment with resveratrol reduced AhR recruitment in a dose-dependent fashion, prevented the TCDD-dependent repression of BRCA-1 transcription and restored BRCA-1 protein expression. The treatment with TCDD induced the recruitment of histone deacetylase-1, DNA methyltransferase-1, methyl-binding protein-2, and reduced the association of acetylated histone-4 and acetylated histone-K9. These effects were abrogated by cotreatment with resveratrol. We propose that dietary antagonists of the AhR such as resveratrol may be useful in the prevention of epigenetic BRCA-1 silencing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1115.
Abstract 1128: The tumor suppressive function of Merlin/Nf2 is mediated by a novel tight junction-associated protein complex
Authors: Yi Chunling , Kissil Joseph 
Published: February 2011

Abstract
Mutations in the NF2 tumor suppressor gene lead to inherited cancer-disorder Neurofibromatosis Type 2 (NF2) and other sporadic nerve-sheath tumors. Merlin, the protein product of the NF2 gene, suppresses cell proliferation and tumorigenesis by regulating multiple signaling pathways including the Ras-MAPK pathway. Through affinity purification, we have identified a novel tight-junction-associated protein complex comprising Merlin and a number of tight junction associated proteins. We show that Merlin directly interacts and co-localizes with one of these tight junction proteins through their mutual coiled-coil domains in epithelial and Schwann cells. Furthermore, the two proteins co-localize to paranodes and Schmidt-Lantermann incisures in myelinated peripheral nerve, the most frequent site of tumor development caused by Nf2 inactivation. We establish that the novel Merlin-binding protein functions downstream of Merlin as a positive regulator of Rac1 activity and the Ras-MAPK signaling. Importantly, we are able to demonstrate that depletion of this Merlin-interacting protein in Nf2-/- schwannoma cells down-regulates the Ras-MAPK signaling pathway, and impedes cellular proliferation in vitro and tumor development in vivo. Taken together with our observations that several NF2 patient-derived mutant Merlin proteins exhibit diminished association with this protein and that its level is elevated in 9 out of 10 human schwannoma samples examined, we conclude that the novel Merlin-binding partner identified in this study mediates the tumor suppressive function of Merlin and represents a potential therapeutic target for NF2 related tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1128.
Abstract 113: The TCGA proneural subtype predicts improved clinical outcome for low-grade oligodendrogliomas
Authors: Moreno Carlos S. , Cooper Lee , Cholleti Sharath R. , Gutman David , Kurk Tahsin , Brat Daniel J. , Saltz Joel H. 
Published: February 2011

Abstract
The Cancer Genome Atlas Project (TCGA) has produced a wide array of omic data on glioblastoma multiforme (GBM) tumors, and has resulted in several works on the molecular subtyping of GBM tumors. Despite its richness, the TCGA dataset currently contains very limited data for low-grade gliomas and progressive GBMs, preventing analysis of progression models and prognostic biomarker discovery for these tumor types. A complementary dataset, the NCI Repository for Molecular Brain Neoplasia Data (REMBRANDT), includes a collection of samples for low-grade and progressive gliomas. This data contains some paired tumors that progressed to GBM and like TCGA, includes pathological and survival information. Our in silico study of low-grade and progressive gliomas has leveraged this complementary data to examine the progression of low-grade gliomas to GBM. The REMBRANDT dataset includes 176 samples with survival outcome data, including 101 grade IV GBM, 32 astrocytomas, and 43 oligodendrogliomas. Of the astrocytomas and oligodendrogliomas, there are 31 grade II samples and 31 grade III samples, with the remainder lacking grade data. We have investigated the gene expression profiles of the REMBRANDT samples to compare them to the established classes from TCGA and other studies. Candidate prognostic biomarkers have been identified to predict the progression of low-grade gliomas. We have found that the TCGA Proneural subtype predicts improved clinical outcome for low-grade oligodendrogliomas, with significantly better survival among all 176 low and high-grade samples (log rank test p = 1.27e-08). Moreover, analysis of 62 grade II and grade III samples determined that the Proneural class still has significantly better outcome (p= 0.0033). Further sub-analysis to control for oligodendrogliomas and grade, found that grade III oligodendrogliomas with the Proneural signature still had significantly improved survival (p &lt; 0.05, n = 12). Stratification using the signatures developed by Li et al that define six oligodendrioma and glioma subtypes demonstrated that the OA subclass had significantly better survival (log rank test p = 9.14e-08). However, these signatures were not significant in multivariate analysis after controlling for grade and disease subtype. Thus, the gene expression patterns identified in the TCGA analysis of GMB has intrinsic prognostic value for low-grade oligondendriomas, and likely represents important differences in tumor biology with implications for treatment and therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 113.
Abstract 1133: Inactivation of BRG1 in non-small cell lung cancer (NSCLC) cell lines
Authors: Zhang Wei , Valencia Ilse , Yan Jingsheng , Chari Raj , Girard Luc , Soh Junichi , Tam Kit , Xie Yang , Lam Wan , Minna John , Gazdar Adi 
Published: February 2011

Abstract
Purpose: To study the frequency and gene expression profile of BRG1 inactivation in NSCLC cell lines. Background: BRG1 is the catalytic subunit of SWI/SNF chromatin remodeling complex and provides ATPase activity necessary for transcriptional regulation of many genes. BRG1 is frequently inactivated in lung cancers and loss of BRG1 correlated with poor prognosis. Methods: Forty NSCLC cell lines containing various gene mutations were analyzed. BRG1 cDNA was sequenced and SNP analysis was used to confirm the large deletion mutants. Gene expression profile was determined by Illumina human WG-6 V3 beadchip (detecting ∼ 48,000 transcripts, ∼25,000 genes). BRG1 mRNA levels were determined by both RNA microarray and qPCR methods. BRG1 protein expression was analyzed by immuno-blotting. Results: Thirteen of forty (33%) NSCLC cell lines had no BRG1 protein expression (n =11) or expressed abnormal size of BRG1 (n =2). BRG1 cDNA was sequenced in these cell lines as well as control cell lines. While 10 control cell lines with normal BRG1 protein expression were not found to contain mutations, eleven cell lines without BRG1 protein expression and one containing abnormal size BRG1 protein were found to have mutations, including deletions, point mutations and insertion. The deletions and point mutations of BRG1 are homozygous. Mutant BRG1 expressed either no or lower than normal levels of BRG1 mRNA. BRG1 inactivation was found more frequent in smokers (50%) than non-smokers (15%), and coexisted with KRAS mutation, but was mutually exclusive to EGFR mutation. Furthermore, inactivation of BRG1 and LKB1, a tumor suppressor gene also located on chromosome 19p and adjacent to BRG1, showed 73% concordance (P=0.03). Finally, RNA microarray analysis showed nearly 800 transcripts (False Discovery Rate &lt;5%) down or up regulated in NSCLC cell lines with BRG1 inactivation compared to cell lines with wild type BRG1. Conclusions: 1) BRG1 is frequently mutated in NSCLC cell lines by deletions or point mutations. 2) There is excellent concordance (98 %) between mutation status and loss of protein expression. 3) Inactivation of BRG1 shows concordance with smoking history and LKB1 mutation, and is negatively correlated with EGFR mutation. 4) Inactivation of BRG1 has a major impact on gene expression profile of NSCLC cell lines. These data indicate that BRG1 may play an important role in lung tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1133.
Abstract 1134: Analysis of the tumor supressor role of BRG1 in lung cancer
Authors: Romero-Ferraro Octavio A. , Gimenez-Xavier Pol , Morris Stephanie , Jhon Sam , Hager Gordon L. , Sanchez-Cespedes Montserrat 
Published: February 2011

Abstract
The BRG1 protein features a bromodomain and helicase/ATPase activity and is a central component of the SWI/SNF chromatin remodeling complex. At present, the tumor suppressor role of the BRG1 gene, also called SMARCA4, is strongly supported by several genetic and functional observations. First of all, somatic and homozygous genetic inactivation of BRG1 has been observed in a variety of cancer cell lines and studies in lung cancer cells have estimated the frequency of BRG1 inactivation in about thirty per cent of this tumor type. Here we have cloned two BRG1 mutations, lacking the ATPase domain, found in lung cancer cell lines. One of these is a missense change in a highly conserved aminoacid within the ATPase domain (W764R) identified in the NCI-H2126 cell line while the other is an in-frame deletion (E668-Q758 del) identified in the NCI-H1703 cell line. We have studied the capability of these mutations to affect the biological function of BRG1 and compared the efficiency of the wild type BRG1 and that of the two mutants in reducing cell growth in cancer cells. To determine the effect of these mutations on the activity of BRG1 we took advantage of a transcription reporter assay in the human lung carcinoma cell line (NCI-H1299) that lacks wild type BRG1 due to a homozygous mutation. In this system, the simultaneous transfection of the BRG1 constructs and a construct carrying the MMTV-Luciferase reporter plasmid and a GR (glucocorticoid) expression plasmid allows the determination of the contribution of BRG1 to the hormone-dependent regulation of MMTV transcription. Transfection of H1299 cells with these constructs resulted in an eightfold increase of MMTV transcription in the presence of hormone when the cells were transfected with the wild type BRG1 as compared as to the cells transfected with either the mutants or the empty vectors. In addition, we observed that overexpression of wild type BRG1, but not the mutant proteins, in several lung cancer cell lines lead to cell growth suppression. Thus, our present data support an important role of BRG1 tumor suppressor gene in cancer development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1134.
Abstract 1135: Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer
Authors: Park Yoonsoo , Coxon Amy , Komiya Takefumi , Chen Wei-Dong , Zajac-Kaye Maria , Meltzer Paul , Karpova Tatiana , Kaye Frederic 
Published: February 2011

Abstract
Activation of Crtc1 (also known as Mect1/Torc1) by a t(11;19) chromosomal rearrangement underlies the etiology of malignant salivary gland tumors. Since LKB1 is a target for mutational inactivation in lung cancer and was recently shown to regulate hepatic Crtc2/CREB transcriptional activity in mice, we now present evidence suggesting disruption of an LKB1/Crtc pathway in cancer. Although Crtc1 is preferentially expressed in adult brain tissues, we observed elevated levels of steady-state Crtc1 in thoracic tumors. In addition, we demonstrate that somatic loss of LKB1 is associated with underphosphorylation of endogenous Crtc1, enhanced Crtc1 nuclear localization, and enhanced expression of the Crtc prototypic target gene, NR4A2/Nurr1. Inhibition of NR4A2 was associated with growth suppression of LKB1-null tumors, but showed little effect on LKB1-wildtype cells. These data strengthen the role of dysregulated Crtc as a bona fide cancer gene, present a new element to the complex LKB1 tumorigenic axis, and suggest that Crtc genes may be aberrantly activated in a wider range of common adult malignancies.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1135.