bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3084: Constitutively active RAS signaling reduces 1,25 dihydroxyvitamin D-mediated gene transcription by suppressing vitamin D receptor gene expression in mouse colon epithelial cells
Authors: DeSmet Marsha , Fleet James C. 
Published: August 2012

Abstract
The active metabolite of vitamin D, 1,25 dihydroxyvitamin D (1,25(OH)2D), binds to the vitamin D receptor (VDR) and stimulates anti-cancer transcriptional events in many cell lines including colon cancer cells. However, we found that tumors which form in the distal colon of mice with an APC allele deletion had significantly lower VDR mRNA levels compared to RNA isolated from the distal colon of wild-type mice (-92%, p≤0.05). These data suggest that colon carcinogenesis may impair 1,25(OH)2D-regulated chemoprevention in colon epithelial cells. APC inactivation and KRAS activation are early events in the development of distal colon that may suppress VDR gene expression. Compared to immortalized colonic epithelial cells derived from the “Immorto” mouse (YAMC), cells from a cross between APCmin and “Immorto” mice (IMCE), and YAMC cells overexpressing the v-Ha-RAS gene (YAMC-RAS) have significantly lower VDR mRNA (-80%; p≤0.05) expression. Previous research shows that constitutively active (ca) RAS signaling suppresses 1,25(OH)2D action in many cell lines so we conducted additional studies on the impact of this mutation. YAMC-RAS cells had a significant reduction in 1,25(OH)2D-induced CYP24 mRNA expression (-40%; p≤0.05). Consistent with lower VDR mRNA levels, YAMC-RAS cells also had lower VDR protein levels than YAMC cells and the suppression of 1,25(OH)2D-induced CYP24 expression in YAMC-RAS was overcome with VDR over-expression. The mechanism for RAS-mediated suppression of VDR mRNA levels was further explored. First we hypothesized that caRAS signaling expression reduced VDR mRNA stability, however, YAMC and YAMC-RAS cells treated with 4 µg/ml of the transcription inhibitor actinomycin D for up to 12 h had no significant difference in the VDR mRNA half-life (about 8 h). Next we examined whether caRAS signaling reduced accessibility within chromosomal regions in the VDR gene previously identified as necessary for VDR gene expression. Using a DNAse I hypersensitivity assay we found that in YAMC-RAS cells there was a significant reduction (p≤0.05) in chromosome accessibility on the proximal promoter (-23%, 300 bp upstream of exon 1), an enhancer region located 6 kb upstream of the transcriptional start site (-56%), and an enhancer region located in exon 2 (-100%) compared to the YAMC cells. These data show that caRAS signaling suppresses 1,25(OH)2D-mediated gene transcription in colon epithelial cells by reducing VDR gene transcription. Supported by NIDDK Award DK54111and AICR Award 09A098 to JCF
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3084. doi:1538-7445.AM2012-3084
Abstract 3086: α-arrestin-1 acts as a nuclear transcriptional regulator of endothelin A receptor signalling to promote ovarian cancer progression
Authors: Rosanò Laura , Cianfrocca Roberta , Tocci Piera , Spinella Francesca , Castro Valeriana Di , Salvati Erica , Biroccio Anna Maria , Natali Pier Giorgio , Bagnato Anna 
Published: August 2012

Abstract
In epithelial ovarian cancer (EOC), endothelin (ET)-1/endothelin A receptor (ETAR) autocrine loop activates epithelial to mesenchymal transition (EMT) and malignant progression through the activation of β-catenin-driven transcriptional programs. Although it has been demonstrated that α-arrestin-1 (α-arr1) is involved in ETAR signalling acting as cytoplasmic scaffold protein, the specific contribution to ETAR-regulated EOC progression in the nuclear compartment remains undefined. In this study, we demonstrated that in response to ETAR activation by ET-1, endogenous as well as exogenous α-arr1 translocated to the nucleus in different EOC cell lines. To study a putative role of α-arr1 in controlling gene expression, we investigated the relationship of α-arr1 with β-catenin. We found that ET-1-driven α-arr1 nuclear translocation is associated with a nuclear translocation of with β-catenin and their physical interaction, as shown by microscopy and biochemical analysis. This nuclear complex, that include TCF4 transcription factor, is localized in ET-1-dependent manner on the promoter regions of specific β-catenin target genes, such as ET-1, matrix-metalloproteinase-2, and Cyclin D1, thus promoting their transcription. Gain/loss of function approaches as well as nuclear mutant α-arr1 expression demonstrated that this complex is critical for the recruitment and binding of p300 acetyltransferase on these promoters, resulting in enhanced H3 and H4 histone acetylation, enhanced promoter activity and gene expression, specifically required for ETAR-induced cell migration, invasion, and EMT. In a murine orthotopic model of metastatic human EOC, silencing of α-arr1 or expression of nuclear mutant α-arr1, as well as ETAR blockade, by the specific antagonist zibotentan, inhibits metastasis and intravasation. Finely, in human EOC tissues, α-arr1/β-catenin nuclear complexes are selectively enriched at specific gene promoters compared to non-tumoral ovarian tissues. Therefore, our study provides insights into how a nuclear α-arr1-mediated epigenetic mechanism controls β-catenin activity in response to ETAR activation, deciphering a novel function for α-arr1 as signal transducer for the nuclear compartmentalization of ETAR signalling in promoting tumor metastasis. Supported by AIRC, AstraZeneca
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3086. doi:1538-7445.AM2012-3086
Abstract 3089: Regulation of GFI proteins by Notch intracellular domains
Authors: Andrade Daniel L. , Bareyan Diana , Singer Jason , Quinton Ryan , Engel Michael 
Published: August 2012

Abstract
Growth factor independence (GFI)-1 and its homolog, GFI1B, are transcriptional regulators that play critical roles during hematopoiesis. GFI family proteins are characterized by near-invariant SNAG and zinc finger domains that direct transcriptional repression and DNA-binding, respectively. A linker region with limited homology and unknown function separates the conserved SNAG and zinc-finger regions. GFI proteins display distinct expression patterns within the myelo-erythroid compartment and make similarly distinct contributions to cell fate specification. GFI1 expression is necessary for hematopoietic stem cell maintenance and is required for granulocytic differentiation beyond the promyelocyte stage. Enforced expression of GFI1 promotes IL-2-independent growth of hematopoietic progenitors and inhibits apoptosis. Mutations in GFI1 lead to a severe congenital neutropenia syndrome that carries an increased risk of myeloid leukemia development. GFI1B expression predominates in erythroid and megakaryocytic precursors and is required for terminal differentiation along both lineages. Moreover, elevated GFI1B expression occurs preferentially in erythroid and megakaryoblastic leukemias, and contributes to the malignant phenotype by supporting growth and preventing apoptosis. Given their complementary roles as growth and survival factors, yet distinct contributions to lineage allocation in hematopoiesis, it is essential to define how GFI family proteins are integrated into the signaling machinery governing cell fate specification. We show that both GFI1 and GFI1B interact with intracellular domains of Notch receptors. Enforced expression of the Notch1 intracellular domain (N1-ICD) impairs GFI-mediated transcriptional repression. Using deletion mutagenesis, we have mapped the regions required for the N1-ICD–GFI1 interaction. Both the ankyrin repeat and transactivation domains of N1-ICD contribute binding surfaces for GFI1. In reciprocal mapping experiments, we show that N1-ICD binding to GFI1 requires a 128-amino acid motif in the divergent linker region near the zinc finger repeat elements. This region contains a high probability consensus sumoylation element that is absolutely conserved in mammalian species but not present in GFI1B. These data suggest that Notch activation may directly impact transcriptional targets regulated by GFI family proteins and expand the potential sphere of influence for Notch in hematopoietic development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3089. doi:1538-7445.AM2012-3089
Abstract 309: Induction of activation-induced cytidine deaminase (AID) by dendritic cells leads to genomic instability in human myeloma
Authors: Koduru Srinivas , Wong Ellice , Strowig Till , Sundaram Ranjini , Zhang Lin , Strout Matthew P. , Flavell Richard A. , Schatz David G. , Dhodapkar Kavita M. , Dhodapkar Madhav V. 
Published: August 2012

Abstract
Tumor microenvironment (TME) is often implicated in regulating the growth of tumors, but whether it can directly alter the genetics of tumors is not known. Myeloma is a plasma cell malignancy characterized by growth of tumor cells in the bone marrow. Prior studies have shown that genomic instability and dendritic cell (DC) infiltration are common features of human myeloma (MM). Mechanisms underlying genomic instability in MM are largely unknown. Here we show that the interaction between myeloma and DCs but not monocytes, leads to rapid induction of the genomic mutator AID and AID-dependent DNA double-strand breaks (DSBs) in myeloma cell lines as well as primary MM cells. Both myeloid as well as plasmacytoid DCs known to infiltrate MM lesions have the capacity to induce AID in MM tumor cells. The induction of AID and resultant DNA-DSBs in tumor cells by DCs depends on DC-tumor contact and is inhibited by the blockade of RANK/RANKL interactions. DC-mediated genomic damage in tumors also leads to altered tumorigenicity in vivo. These data demonstrate a novel pathway for the capacity of specific cells in TME such as DCs to regulate genomic integrity in cancer. These findings also suggest that DC-mediated genomic instability may be targetable by approaches such as RANKL inhibition that are already in the clinic.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 309. doi:1538-7445.AM2012-309
Abstract 3090: Oncogenic ETS transcription factors bind ETS/AP-1 sequences and activate a RAS/MAPK gene expression program in the absence of MAPK activation
Authors: Hollenhorst Peter C. , Ferris Mary W. , Hull Megan A. , Chae Heejoon , Kim Sun , Graves Barbara J. 
Published: August 2012

Abstract
Deciphering the mechanism of transcription factor function in both normal and disease states requires understanding how these proteins are targeted to specific genomic binding sites, influence transcription, and how these functions are modified by signaling pathways. However, overlapping functions among the thousands of transcription factors encoded by the human genome have made it difficult to assign specific mechanisms. Approximately 50% of prostate cancers have chromosomal rearrangements resulting in the over-expression any one of four ETS-family transcription factors. It is not known why these four ETS family members are associated with prostate cancers, while the other 24 human ETS genes are not. We found that the four oncogenic ETS family members have a specific role in prostate cell migration that does not extend to other family members. Using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq), this specific biological function was matched to a specific set of genomic targets highlighted by the presence of both ETS and AP-1 binding sequences. ETS/AP-1 binding sequences are prototypical RAS-responsive elements where a MAPK can phosphorylate ETS proteins increasing transcriptional activation. We found that oncogenic ETS proteins could activate a RAS/MAPK transcriptional program when the MAPK pathway was inactive. These findings indicate that a specific function of ETS proteins over-expressed in prostate cancer is the activation of a RAS/MAPK gene expression program in the absence of activating mutations in the RAS/MAPK signaling pathway. We propose that this ETS/AP-1 regulated, RAS-responsive, transcriptional network will also play a critical role in other cancers that do not over-express an ETS protein, but have activating mutations in the RAS/MAPK pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3090. doi:1538-7445.AM2012-3090
Abstract 3094: Interferon-α induced TLR4 is indispensable for the synergistic induction of Duox2/DuoxA2 by lipopolysacharide (LPS) and IFN-γ in human pancreatic cancer cells
Authors: Wu Yongzhong , Lu Jiamo , Antony Smitha , Juhasz Agnes , Liu Han , Jiang Guojian , Roy Krishnendu , Doroshow James 
Published: August 2012

Abstract
Several bacterial cell wall components, including lipopolysaccharide (LPS), muramyldipeptide (MDP), and flagellin, have been shown to engage their corresponding receptors and mediate NADPH oxidase (NOX)-dependent reactive oxygen species (ROS) generation that may be involved in wound healing, host defense, and the inflammatory response in airway and gastrointestinal epithelial cells. Previously, we reported that two human pancreatic cancer cell lines, BxPC-3 and AsPC-1, respond to the pro-inflammatory cytokine IFN-γ by upregulating the expression of both Dual oxidase 2 and its cognate cofactor DuoxA2 resulting in enhanced ROS production. It has also been reported that human pancreatic cancer cells express TLR4/MyD88, and that signaling downstream of the TLR receptor may be responsible for LPS-induced invasiveness of pancreatic cancer cells. In our studies, we have demonstrated that IFN-γ up-regulates TLR4 and its adaptor protein MyD88 expression in BxPc-3 cells and augments the response of these cells to LPS, resulting in the activation of NFkB signaling, enhancing p65 subunit accumulation in the nucleus. Moreover, we found that p65 binds to the Duox2 promoter, and cooperates with the IFN-γ- induced Stat1 expression to synergistically enhance Duox2/DuoxA2 expression, leading to persistent intra- and extracellular ROS accumulation. TLR4 silencing by RNAi and two independent NF-kB inhibitors (PDTC and BAY11-70829) specifically attenuate LPS- and IFN-γ-mediated Duox2 expression in BxPc-3 cells, underscoring the importance of TLR4 engagement and the activation of NF-kB signaling in regulating Duox2 expression and subsequent ROS generation by LPS and IFN-γ. Our data suggest that sustained extracellular H2O2 accumulation, mediated by LPS- and IFN-γ- induced Duox2/DuoxA2 expression, may contribute to the deleterious effects of cytokine-mediated pancreatic inflammation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3094. doi:1538-7445.AM2012-3094
Abstract 3102: Hexavalent chromium induces chromosome instability leading to DNA double strand break repair deficiency and neoplastic transformation
Authors: Wise Sandra S. , Holmes Amie L. , Xie Hong , Thompson W. Douglas , Wise John P. 
Published: August 2012

Abstract
Chromosome instability (CIN) is a hallmark of lung cancer with cells exhibiting both translocations and aneuploidy. Hexavalent chromium (Cr(VI)) is a well known respiratory carcinogen. The ability of Cr(VI) to induce chromosomal translocations is unknown. We exposed human lung cells to lead chromate for three sequential 24 h periods, each separated by about a month. After each treatment, cells were seeded at colony forming density, cloned, expanded and retreated. Each generation of clones was tested for chromium sensitivity, chromosome complement, ability to repair DNA double strand breaks (DSB), and growth in soft agar. We found that after the first treatment, lead chromate-treated cells exhibited a normal chromosome complement though a few clones showed a decrease in cell survival. After the second exposure, more than half of the clones acquired an abnormal karyotype including numerical and structural changes. The third treatment resulted in additional abnormal clones as well as previously abnormal clones acquiring more abnormalities. Clones were treated with soluble Cr(VI) for 24 h followed by a 24 h recovery period to measure DNA DSB repair. Abnormal clones showed persistent H2A.X and 53BP1 foci formation after 24 h recovery suggesting that these clones had acquired a DNA DSB repair-deficient phenotype. In addition, clones from the third generation were able to form colonies in soft agar suggesting that the cells have neoplastically transformed. This work was supported by NIEHS grant ES016893 (J.P.W.) and the Maine Center for Toxicology and Environmental Health.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3102. doi:1538-7445.AM2012-3102
Abstract 3115: PARP overactivation predicts the susceptibility of human cancer cells to apoptosis induction by PARP inhibitors
Authors: Michels Judith , Vitale Ilio , Galluzzi Lorenzo , Kepp Oliver , Senovilla Laura , Olaussen Ken André , Soria Jean-Charles , Castedo Maria , Kroemer Guido 
Published: August 2012

Abstract
Chemical inhibitors of poly(ADP)ribose (PAR) polymerases (PARP) have generated raising expectations in cancer treatment, either as monotherapeutic agents for the therapy of tumors that are deficient in DNA repair by homologous recombination, or combined with DNA-damaging compounds. Results from early clinical trials suggest that PARP inhibitors are well tolerated, and would be particularly useful for BRCA1- and BRCA2-mutated tumors. However, as these tumors constitute a minor fraction of all cancers, the main challenge is to extend the efficacy of PARP inhibitors to BRCA-proficient tumors, calling for the need of reliable biomarkers that predict the efficiency of PARP inhibitor-based therapy. Here, we report the effects of two chemically distinct PARP inhibitors, the phenanthridinone PJ34 and the 4-methoxy-carbazole derivate CEP8983, on non-small cell lung cancer (NSCLC) cells exhibiting increased PARP activity. We found that PAR polymers are a predictive marker of the sensitivity of NSCLC cells to PARP inhibitors. We were able to confirm these findings in mesothelioma, cervical cancer and ovarian cancer cell lines that are characterized by constitutively increased expression of PARP (as monitored by immunoblotting with a PARP1-specific antibody) as well as enhanced PARP enzymatic activity (as detected by immunoblotting with an antibody that recognizes poly(ADP)ribosylated proteins). Upon treatment with PARP inhibitors, cells with hyperactivated PARP exhibited signs of DNA damage (as assessed by immunofluorescence microscopy with an antibody that recognizes the phosphorylated form of histone 2AX) and underwent cell death via the intrinsic pathway of apoptosis (as monitored by immunofluorescence microscopy with antibodies for the detection of cytochrome c and active caspase-3). The chemosensitizing or cell death-inducing effects of PJ34 and CEP8983 were mimicked by PARP1- and PARP2-specific siRNAs, suggesting that they are indeed mediated by PARP inhibition. Moreover, PARP inhibitors efficiently reduced the growth of NSCLC xenografts exhibiting increased PARP activity (as evaluated by immunohistochemistry for poly(ADP)ribosylated proteins on paraffin embedded xenografts). Altogether, our results indicate that PARP overactivation reflects the susceptibility of NSCLC cells to apoptosis induction by PARP inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3115. doi:1538-7445.AM2012-3115
Abstract 3176: miR-211 promotes the progression of head and neck carcinomas by targeting TGFβRII
Authors: Chu Ting-Hui , Chang Kuo-Wei 
Published: August 2012

Abstract
Head and neck squamous cell carcinoma (HNSCC) is among the prevalent neoplasms in the world. More than 50% patients die within 5 years after initial therapy due to local recurrence, invasion or metastasis. Previous studies have shown that transforming growth factor-beta type II receptor (TGFβRII) deprivation could promote HNSCC metastasis. Our histolopathological analysis revealed that TGFβRII was down-regulated in metastatic tumors relative to primary HNSCC. This study aimed to address the roles of microRNAs in regulating TGFβRII for HNSCC progression. In silico modules predicted that miR-211 and miR-370 might target TGFβRII. TGFβRII was further confirmed to be a target of miR-211 in HNSCC cells by means of reporter assay, quantitative RT-PCR analysis and Western blot analysis. Interestingly, TGFβRII and miR-211 were inversely expressed during the metastasis process of HNSCC. In HNSCC cell lines, the inhibition of TGFβRII by miR-211 attenuated the Smad3 phosphorylation and increased cell migration, while ectopic Smad3 expression decreased cell migration drastically. In agreement with previous findings that the disruption of TGFβ/Smad pathway could benefit HNSCC progression, this study further specified that miR-211 played crucial regulatory roles in the suppression of TGFβ/Smad pathway for HNSCC progression by targeting TGFβRII. To elucidate the in vivo oncogenic role of miR-211 in HNSCC carcinogenesis, we established K14 promoter driven miR-211 transgenic mice with stable expression of miR-211 in the basal epithelial layers of skin and oral mucosa. By administrating of 4-nitroquinoline 1-oxide in drinking water to induce tongue tumors, the transgenic mice exhibited higher potential for the induction and advances of tumors relative to controls. This study concludes that miR-211 promotes HNSCC progression by targeting TGFβRII and intercepting TGFβ/Smad signaling pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3176. doi:1538-7445.AM2012-3176