bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 763A: SUMOylation of ATF3 alters MC2R, NR5A1, STAR, and TP53 gene activities.
Authors: Wang Chiung-Min , Brennan Victoria , Gutierrez Ninoska , Wang Xirui , Wang Lizhong , Yang Wei-Hsiung 
Published: August 2014

Abstract
Cyclic AMP-dependent transcription factor-3 (ATF3), a stress sensor/mediator, plays an essential role in cells to maintain homeostasis and has diverse functions in cellular death and survival signal pathways. ATF3 binds to the consensus ATF/cAMP response element (CRE) to regulate its downstream target genes, such as CCNE2 (Cyclin E2), CD82 (KAI1), DDIT3 (GADD153), LDLR (LDL receptor), SNAI1, TP53, and TWIST1. A previous report has shown that the activities of ATF3 are modulated by ubiquitination; however, whether it is modified by small ubiquitin-related modifier (SUMO), an important modification in regulating a wide range of cellular processes, remains unknown. The aim of this study was to investigate whether ATF3 is post-translationally modified by SUMO proteins and also to determine the role of SUMOylation of ATF3 on MC2R, NR5A1, STAR, and TP53 gene activities. Here we demonstrate that ATF3 is clearly defined as a SUMO target protein both in vitro SUMOylation assay using recombinant proteins and at the cellular levels. Furthermore, ATF3 interacted with UBE2I (Ubc9), the only SUMO E2 enzyme found so far. In addition, PIAS3β (a SUMO E3 ligase) enhanced and SENP2 and SENP7 (two SUMOylation proteases) decreased SUMOylation of ATF3, respectively. In addition, we found that ATF3 is selectively SUMOylated at lysine residue 42 but the SUMOylation/deSUMOylation does not alter subcellular localization of ATF3. We next characterized the functional role of ATF3 SUMOylation on MC2R, NR5A1, STAR, and TP53 gene expression. We found that SUMOylation of ATF3 is required for full repression of NR5A1 and TP53 genes. While SUMOylation of ATF3 is required for full activation of MC2R gene activity, SUMOylation of ATF3 further enhances repression of STAR gene activity. Overall, we provide the first evidence that ATF3 is post-translationally modified by SUMO to regulate MC2R, NR5A1, STAR, and TP53 gene activities.
Citation Format: Chiung-Min Wang, Victoria Brennan, Ninoska Gutierrez, Xirui Wang, Lizhong Wang, Wei-Hsiung Yang. SUMOylation of ATF3 alters MC2R, NR5A1, STAR, and TP53 gene activities. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 763A. doi:10.1158/1538-7445.AM2013-763A
Abstract 769: Integrin-Linked Kinase (ILK) breaks Merlin's spell to inhibit the Hippo tumor suppressor pathway and activate the YAP oncogene.
Authors: Serrano Isabel , Muller William J. , Dedhar Shoukat 
Published: August 2014

Abstract
The Hippo signalling pathway is gaining recognition as an important player in tumor progression. Components of the pathway, which include transcriptional co-activators YAP/TAZ, are dysregulated in a significant fraction of human cancers, and YAP activation has recently been shown to promote Epithelial to Mesenchymal Transition (EMT) and metastasis. However, how Hippo signalling is dysregulated in tumors remains unclear. Here, we demonstrate that Integrin-Linked Kinase (ILK), an actin-interacting, focal adhesion adaptor and serine/threonine protein kinase whose expression is also significantly upregulated in many types of cancers, inhibits the Hippo tumor suppressor pathway by stimulating the phosphorylation, and inhibiting the activity of Merlin, via the protein phosphatase inhibitor, CPI-17, an established target of ILK, and an inhibitor of Merlin (Deng JT et al. Biochem J 2002; Huang J et al. Biochem J 2006). We have assessed the pathway in human breast and prostate cancer cell lines, in which the Hippo pathway is switched OFF, as determined by the phosphorylation status of Merlin, MST1/2, LATS1/2, and YAP, and the nuclear YAP localization. We demonstrate that inhibition of ILK expression, or inhibition of its activity in these cells turns the Hippo pathway ON, resulting in the stimulation of YAP phosphorylation, sequestration in the cytoplasm, and inhibition of TEAD transcriptional activity. In addition, we have determined that YAP/TAZ protein expression is significantly upregulated in vivo in ErbB2 induced mammary tumors from transgenic mice, and that deletion of ILK from these tumors, which significantly delays tumor growth and inhibits metastasis, dramatically suppresses the expression of these transcription co-activators. Finally, we demonstrate that ILK plays a critical role in the suppression of the Hippo pathway by TGF-b, EGF and LPA. Treatment of human breast and prostate epithelial cells with these growth factors results in dephosphorylation of LATS 1/2, and YAP, and nuclear localization of YAP. However, inhibiting ILK activity under these conditions results in the stimulation of phosphorylation of LATS1/2 and YAP, as well as in the sequestration of YAP/TAZ in the cytoplasm. These novel data demonstrate that ILK inhibits the Hippo tumor suppressor pathway leading to nuclear activation of YAP/TAZ, thereby contributing to tumor progression and metastasis.
Citation Format: Isabel Serrano, William J. Muller, Shoukat Dedhar. Integrin-Linked Kinase (ILK) breaks Merlin's spell to inhibit the Hippo tumor suppressor pathway and activate the YAP oncogene. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 769. doi:10.1158/1538-7445.AM2013-769
Abstract 77: Genetic variations in the stem cell pathway predict for toxicity following radiotherapy in lung cancer.
Authors: Skinner Heath D. , Pu Xia , Chang Joe , Lu Charles , Komaki Ritsuko , Wu Xifeng 
Published: August 2014

Abstract
Lung cancer is a devastating malignancy leading to over 150,000 deaths in the US annually. One primary modality in the treatment of locally advanced lung cancer is radiotherapy in combination with chemotherapy. However, this treatment can lead to significant local toxicity in as many as 50% of all patients and, in some cases, is fatal. Though post-radiation toxicity significantly affects adherence to treatment, quality of life and clinical outcome, it is difficult to predict. Further, no genetic markers have yet been found to be useful in a clinical setting. Because stem cell recruitment is part of the post-radiation tissue repair response, we hypothesize that alterations in stem cell signaling may predict for toxicity following radiotherapy. To investigate this question we examined 441 SNPs related to stem cell signaling in the peripheral blood lymphocytes in 159 patients with stage III-IV lung cancer treated with chemoradiotherapy. After adjusting for treatment-related and demographic factors, we found 47 SNPs significantly associated with symptomatic radiation pneumonitis (p&lt;0.05) and 51 SNPs associated with symptomatic esophagitis (p&lt;0.05). For example, patients with at least one risk allele for WNT9Brs:2165846 had a 46% risk of symptomatic pneumonitis, compared to 31% in those who did not, for a 2.23 fold increase in risk (CI: 1.05-4.07, p=0.04). On analysis of a 141 patient validation set with similar characteristics, variant WNT9Brs:2165846 was confirmed to be associated with symptomatic radiation pneumonitis (OR 2.6, CI: 1.1-6.16, p=0.03). Analysis on this confirmation set is ongoing; however, the preliminary results are indicative of the importance of stem cell signaling in modulating repair following radiotherapy and, in combination with clinical factors, may allow for better management of these patients.
Citation Format: Heath D. Skinner, Xia Pu, Joe Chang, Charles Lu, Ritsuko Komaki, Xifeng Wu. Genetic variations in the stem cell pathway predict for toxicity following radiotherapy in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 77. doi:10.1158/1538-7445.AM2013-77
Abstract 771: Pin1 regulates the dynamics of c-Myc DNA binding to facilitate target gene regulation and oncogenesis.
Authors: Farrell Amy , Pelz Carl , Wang Xiaoyan , Daniel Colin , Su Yulong , Janghorban Mahnaz , Impey Soren , Sears Rosalie C. 
Published: August 2014

Abstract
The c-Myc oncoprotein is generally considered to be a master regulator of gene transcription by virtue of its ability to activate or repress the expression of a large percentage of all genes. However, mechanisms that direct c-Myc's recruitment to DNA and target gene selection to elicit specific cellular functions have not been well elucidated. Here, we report that the Pin1 prolyl-isomerase regulates c-Myc transcriptional activity by altering c-Myc's association with target gene promoters. Specifically, we show that Pin1 enhances the recruitment of Serine62-phosphorylated c-Myc along with its co-activators to selected target gene promoters during gene activation, followed by promoting c-Myc's release associated with its degradation, resulting in cyclic c-Myc DNA binding. This facilitates c-Myc's activation of target genes associated with an increase in elongating RNA Polymerase II in the gene body. Genes impacted by this mechanism are involved in cell growth and metabolism, resulting in enhanced pro-proliferative activity, even while controlling c-Myc expression. In cancer cells with impaired c-Myc degradation, Pin1 still regulates cyclic c-Myc DNA binding, even though it no longer enhances c-Myc degradation. This allows for simultaneous high expression of Pin1 and c-Myc in cancer, which can drive a gene expression pattern that we show is enriched in poor outcome subtypes of breast cancer. This study provides new insight into mechanisms regulating c-Myc DNA binding and oncogenic activity, it reveals a novel role for Pin1 in transcription factor regulation, and it elucidates a mechanism that can contribute to oncogenic cooperation between Pin1 and c-Myc.
Citation Format: Amy Farrell, Carl Pelz, Xiaoyan Wang, Colin Daniel, Yulong Su, Mahnaz Janghorban, Soren Impey, Rosalie C. Sears. Pin1 regulates the dynamics of c-Myc DNA binding to facilitate target gene regulation and oncogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 771. doi:10.1158/1538-7445.AM2013-771
Abstract 772: Rap2b, a novel p53 downstream target, promotes cell survival after DNA damage.
Authors: He Yunlong , Li Mangmang , Dubois Wendy , Kovalchuk Alexander , Wu Xiaolin , Huang Jing 
Published: August 2014

Abstract
The tumor suppressor p53 is a critical regulator of apoptosis and cell survival. It evokes both pro-survival and pro-apoptosis programs upon DNA damage. However, the mechanisms underlying this cell fate decision are largely unclear. To identify p53 targets in a global and unbiased manner, we performed gene expression microarray and ChIP-chip assays using mouse embryonic fibroblasts (MEFs) and mouse embryonic stem (mES) cells. I treated MEFs and mES cells with adriamycin, a DNA damage agent, for 8 hours. Comparing to the untreated cells (negative controls), I obtained common genes that were dramatically induced both in MEFs and mES cells. Subsequently, we further analyzed these genes and obtained a list of 90 common genes. Then, I compared these 90 genes with published p53 targets in human cell lines U2OS and HCT116, and found 10 genes (Alox5, Eda2r, Btg2, Mdm2, Adrb2, Cdkn1a, Tnfrsf10b, Rap2b, Ddit4, Bbc3) that are conserved p53 targets between mouse and human. Most of these genes have been well studied except for Rap2b. Both mouse and human Rap2b share the same amino acid residue sequence, which indicating Rap2b might have important conserved functions both in human and in mouse. Using conventional chromatin immunoprecipitation (ChIP) assay and luciferase reporter assay, I identified one p53 binding motif in Rap2b promoter region. After DNA damage, p53 binds to the promoter of Rap2b and activates its transcription. The reduction of Rap2b levels by small interference RNA increases the apoptosis of cells under the damaged condition, suggesting that Rap2b helps cell survive upon DNA damage. This pro-survival role of Rap2b is very similar to the function of another well-known p53 target, Mdm2. Bioinformatic analysis revealed that Rap2b is over-expressed in many types of tumors, consistent with its pro-survival function. Anchorage independent growth assay showed that Rap2b only has weak transformation activity, suggesting that it is not a typical oncogene. Importantly, Rap2b activates RalGDS-Ral survival pathway after DNA damage. Therefore, our results identified a novel player, Rap2b, in the pro-survival program conducted by p53 and revealed a connection between the p53 signaling and the RalGDS-Ral cell survival pathway. Future studies will focus on investigating whether the inhibition of Rap2b may increase the apoptosis of tumor cells.
Citation Format: Yunlong He, Mangmang Li, Wendy Dubois, Alexander Kovalchuk, Xiaolin Wu, Jing Huang. Rap2b, a novel p53 downstream target, promotes cell survival after DNA damage. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 772. doi:10.1158/1538-7445.AM2013-772
Abstract 777: TAp73 depletion unleashes p53-mediated apoptotic response to lethal DNA damage.
Authors: Chen Dongshi , Ming Lihua , Zou Fangdong , Yu Jian , Zhang Lin 
Published: August 2014

Abstract
DNA damage response is essential for maintenance of genomic integrity and functions as a guardian against oncogenic transformation. Ionizing radiation and chemotherapeutic drugs used in anticancer therapies often incur DNA damage in killing of tumor cells. The central regulator of DNA damage response is the tumor suppressor p53, which inhibits cell cycle progression by activating p21 and other cell cycle regulators, or induces apoptosis through proapoptotic targets such as PUMA and Bax. In addition to p53, other p53 family members, such as p73 and p63, also play a significant role in DNA damage response. However, it has remained unclear how coordination of different p53 family members modulates DNA damage response. In this study, we found that sub-lethal levels of DNA damage up-regulated TAp73, the transcriptionally active form of p73, whereas lethal doses of DNA damage triggered TAp73 depletion. In response to mild DNA damage, TAp73 occupied p53 responsive elements in the promoters of p53 target genes to keep the transcriptional activity of p53 in check, which resulted in cell cycle arrest. Following excessive DNA damage, the depletion of TAp73 resulted in enhanced induction of p53 target genes such as PUMA, Noxa and Bax, leading to apoptosis initiation. Furthermore, our results demonstrated that TAp73 depletion after excessive DNA damage was caused by ubiquitin/proteasome-mediated degradation of E2F1, which activates TAp73 expression to maintain cell survival. Collectively, our results suggest that modulation of p53 activity by TAp73 mediates differential responses to genotoxic stress.
Citation Format: Dongshi Chen, Lihua Ming, Fangdong Zou, Jian Yu, Lin Zhang. TAp73 depletion unleashes p53-mediated apoptotic response to lethal DNA damage. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 777. doi:10.1158/1538-7445.AM2013-777
Abstract 787: Tumor suppressor p53 inhibits expression of the pro-metastasis protein Toca-1.
Authors: Chander Harish , Brien Colin D. , Truesdell Peter , Germain Doris , Craig Andrew W. B. 
Published: August 2014

Abstract
Transducer of Cdc42-dependent actin assembly-1 (Toca-1) is an adaptor protein that recruits key actin regulatory proteins to invadopodia in metastatic breast cancer cells. We recently showed that stable silencing of Toca-1 led to reduced invadopodia formation, cell invasion and tumor metastasis in an orthotopic xenograft model in mice. These results raise the possibility that Toca-1 upregulation may occur during tumor progression to metastatic disease. Here we show that Toca-1 expression is higher in triple negative breast cancers (HER2/ER/PR) compared to other subtypes. Since triple negative breast cancers frequently harbor mutations in the tumor suppressor p53, we tested whether p53 regulates Toca-1 expression. In wild-type (WT) p53-expressing normal breast epithelial and breast cancer cells, stabilization of WT p53 by inducing DNA damage, or treating cells with Mdm2 inhibitor Nutlin-3, led to dose-dependent reductions in Toca-1 mRNA and protein expression. Likewise, ectopic expression of WT p53 in p53-null HCC1806 cells also led to repression of Toca-1 levels. To test if this was a direct effect of p53 on the Toca-1 gene, chromatin immunoprecipitation (ChIP) studies were performed. Indeed, the proximal promoter region and intron 2 of the Toca-1 gene (which contained a predicted p53 binding site) were detected in p53 ChIP assays in WT p53-expressing cells, but not mutant p53 expressing breast cancer cells. Together, these results identify a novel pathway to inhibit Toca-1 expression in cells with WT p53, and imply that the loss of p53 in highly metastatic breast cancer subtypes may lead to elevated Toca-1 expression and progression to metastatic disease.
Citation Format: Harish Chander, Colin D. Brien, Peter Truesdell, Doris Germain, Andrew W. B. Craig. Tumor suppressor p53 inhibits expression of the pro-metastasis protein Toca-1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 787. doi:10.1158/1538-7445.AM2013-787
Abstract 79: Immunomodulation in response to radiation-induced lung injury.
Authors: Cappuccini Federica , Wirsdörfer Florian , Drabczyk Malagorzata , Eldh Therese , Sak Ali , Jendrossek Verena 
Published: August 2014

Abstract
Introduction.
Pneumonitis and fibrosis constitute dose-limiting side effects of thorax and whole body irradiation. Although several novel disease biomarkers have been described during recent years, the cellular and molecular factors responsible for disease initiation and progression are still not sufficiently understood. Here, we characterized local and systemic changes in the immune cell compartment in response to radiation-induced lung injury and defined the role of lymphocytes for fibrosis development in a murine model.
Material and methods
A single dose of hemithorax or whole thorax irradiation (15 Gy) was applied on C57BL/6 wild type mice (WT) or immunodeficient RAG-2-/- mice. Mice were sacrificed at defined time points and lungs were isolated for histological and immunohistochemical analysis as well as immune cell phenotyping. Moreover, immune cells were isolated from spleen, blood and cervical lymph nodes and also characterized by flow cytometry. Bronchioalveolar lavage fluid was collected for determination of cytokine levels.
Results and discussion.
Whole thorax irradiation triggered time-dependent changes in the composition and activation state of immune cells isolated from the lung tissue. These changes were paralleled by specific alterations in the cytokines present in the bronchoalveolar lavage fluid. In WT mice whole thorax irradiation with 15 Gy led to a time-dependent increase in collagen deposition and lung fibrosis. Irradiated RAG-2-/- mice showed an earlier onset of collagen deposition and an increased number of fibrotic foci in the lung when compared to WT mice.
Conclusion.
Thorax irradiation triggers local and systemic changes in the composition and the activation state of immune cells. The increased sensitivity of RAG-2-/- mice to radiation-induced fibrosis suggests a role of mature lymphocytes in the suppression of fibrotic changes. An improved understanding of the contribution of specific immune cells to the pathogenic process in the lung may open novel routes to prevent or treat radiation-induced pneumopathy.
Citation Format: Federica Cappuccini, Florian Wirsdörfer, Malagorzata Drabczyk, Therese Eldh, Ali Sak, Verena Jendrossek. Immunomodulation in response to radiation-induced lung injury. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 79. doi:10.1158/1538-7445.AM2013-79
Abstract 799: Global genomic analysis identified PRKCI as a potential therapeutic target gene for human clear cell ovarian cancer.
Authors: Tsang Tsun Yee , Mohapatra Gayatry , Itamochi Hiroaki , Mok Samuel C. , Birrer Michael J. 
Published: August 2014

Abstract
Clear cell ovarian cancer (CCOC), a rare epithelial ovarian cancer histotype, is more resistant to standard chemotherapy and has a worse prognosis than serous and endometrioid histotypes. We attempted to identify genes that are responsible for the aggressive behavior of CCOC and could be potential therapeutic targets using genomic and expression profilings. To identify gene amplification, genome-wide DNA copy number alterations were measured in 13 CCOC cell lines using high-resolution oligonucleotide array CGH (Agilent 105k Human Genome CGH Microarray). GISTIC analysis identified 16 amplified regions containing 391 genes. After comparison to our database of differentially expressed genes between human CCOC specimens and normal ovarian surface epithelium specimen (Affymetrix U133 Plus 2.0 microarrays), 45 of the amplified genes showed mRNA overexpression in CCOC specimens. Among the 45 genes, protein kinase C iota (PRKCI) was amplified in 9/13 CCOC cell lines and was overexpressed (6.7 fold) in CCOC specimens. Analysis using PathwayStudio software identified PRKCI mediated pathways for cell migration and invasion. Knock-down of PRKCI by transfection with PRKCI specific siRNAs suppressed cell migration and invasion in KOC-7c and OVISE cells. On the other hand, ectopic expression of PRKCI by transfection with PRKCI expressing vector enhanced cell migration and invasion in ES2 and TOV21G cells. The results from the present study therefore suggested that PRKCI may promote metastasis and serve as a potential target gene for treatment of human clear cell ovarian cancer.
Citation Format: Tsun Yee Tsang, Gayatry Mohapatra, Hiroaki Itamochi, Samuel C. Mok, Michael J. Birrer. Global genomic analysis identified PRKCI as a potential therapeutic target gene for human clear cell ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 799. doi:10.1158/1538-7445.AM2013-799