bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A14: Transactivation of the Rho-guanine exchange factor ARHGEF2 by oncogenic K-RAS potentiates invasion-migration in pancreatic ductal adenocarcinoma.
Authors: Kent Oliver A. , Vargas Maria Jose Sandi , Rottapel Robbert 
Published: May 2015

Abstract
Activating mutations in K-RAS are a ubiquitous feature of pancreatic ductal adenocarcinoma (PDAC). Cellular transformation by oncogenic RAS engages the MAPK pathway and involves Arhgef2, the microtubule-associated RhoGEF a potential oncogene activated downstream of oncogenic RAS. Using luciferase reporters under regulation by the human ARHGEF2 promoter, we have found that GEF-H1 is regulated by oncogenic K-RAS in multiple cell lines and is a transcriptional target of the MAPK and Jun N-terminal kinase (JNK) pathways. Treatment of cell lines with small molecule inhibitors revealed that promoter activity is dependent on MEK1/2, JNK, and TGF-beta associated kinase (TAK1). We have mapped the human ARHGEF2 promoter and found it contains three regulatory elements: a Ras responsive element (RRE), a “core” ETS transcription factor binding region and two distal PTTG binding sites. The RRE is negatively regulated by the Ras responsive element binding protein 1 (RREB1), a known oncogene regulated by oncogenic K-RAS downstream of the MAPK pathway. The ETS core region contains conserved consensus elements for AP-1, ELK1 and SP1 transcription factors (TF). The pituitary tumor-derived transforming gene (PTTG) has been implicated in PDAC tumorigenesis but its link to oncogenic K-RAS is unknown. Using RNAi and luciferase reporters with mutations in TF binding sites in the ARHGEF2 promoter, we have found the transactivation of ARHGEF2 is dependent on the ELK1 and SP1 transcription factors. Chromatin immunoprecipitation has confirmed association of these transcription factors with the endogenous ARHGEF2 promoter in multiple PDAC cell lines. Our results suggest transactivation of ARHGEF2 by oncogenic K-RAS may lead to increased RhoA activity and by extension, account for the highly metastatic potential of PDAC.
Citation Format: Oliver A. Kent, Maria Jose Sandi Vargas, Robbert Rottapel. Transactivation of the Rho-guanine exchange factor ARHGEF2 by oncogenic K-RAS potentiates invasion-migration in pancreatic ductal adenocarcinoma.. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A14. doi: 10.1158/1557-3125.RASONC14-A14
Abstract A22: An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth
Authors: Young Lucy C. , Hartig Nicole , Munoz-Alegre Marta , Oses-Prieto Juan A. , Durdu Sevi , Bender Sabine , Vijayakumar Vineetha , Rudan Matteo Vietri , Gewinner Christina , Henderson Stephen , Jathoul Amit P. , Ghatrora Rupinder , Lythgoe Mark F. , Burlingame Alma L. , Rodriguez-Viciana Pablo 
Published: May 2015

Abstract
SHOC2 is mutated in Noonan syndrome and plays a key role in the activation of the ERK-MAPK pathway, which is upregulated in the majority of human cancers. SHOC2 functions as a PP1-regulatory protein and as an effector of MRAS. SHOC2 and MRAS form a complex with SCRIB, a polarity protein with tumor suppressor properties. SCRIB functions as a PP1-regulatory protein and antagonizes SHOC2-mediated RAF dephosphorylation through a mechanism involving competition for PP1 molecules within the same macromolecular complex. SHOC2 function is selectively required for the malignant properties of tumor cells with mutant RAS, and both MRAS and SHOC2 play a key role in polarized migration. We propose that MRAS, through its ability to recruit a complex with paradoxical components, coordinates ERK pathway spatiotemporal dynamics with polarity and that this complex plays a key role during tumorigenic growth.
Citation Format: Lucy C. Young, Nicole Hartig, Marta Munoz-Alegre, Juan A. Oses-Prieto, Sevi Durdu, Sabine Bender, Vineetha Vijayakumar, Matteo Vietri Rudan, Christina Gewinner, Stephen Henderson, Amit P. Jathoul, Rupinder Ghatrora, Mark F. Lythgoe, Alma L. Burlingame, Pablo Rodriguez-Viciana. An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A22. doi: 10.1158/1557-3125.RASONC14-A22
Abstract A32: Gaps and opportunities for RASopathies: Use of new tools to make the right choice in target and compound selection
Authors: Rosa Salvatore La , Knight Pamela , Pancza Patrice , Scobie Kimberly , Bakker Annette 
Published: May 2015

Abstract
“RASopathies” are a class of developmental disorders caused by germline mutations in genes that encode protein components of the Ras/MAPK pathway. Each syndrome exhibits different phenotypic features, though there are many overlapping features among syndromes, including characteristic facial features, cardiac defects, cutaneous abnormalities, autism, learning disabilities and a predisposition to malignancies. Neurofibromatosis type 1 (NF1) has been more extensively studied than the other syndromes and today 11 clinical trials are ongoing for NF1 versus 3 in all other RASopathies.
In the last couple of years a few studies were published which directly connected the molecular mechanisms of these diseases to each other, creating a new opportunity to cross-validate the effects of modulating the RAS pathway at different stages and with different tools, and providing new overlapping strategies which could also benefit less studied syndromes. We recently acquired in-house capabilities to access MetaCore and Integrity databases to help in the process of data mining and compound selection. We applied these capabilities in a multi-tiered approach to compare NF1 with Noonan Syndrome (NS). First, we analyzed the molecular profiles of these two RASopathies using MetaCore and zeroed in on a well-known common molecular target, MEK. Among the large number of MEK inhibitors now in development, an analysis of these agents has been made with the use of the database to compare the different chemical classes of inhibitors and analyse properties, opportunities and redundancies among these compounds. The same approach will be then applied to try to identify a novel drug target in common in NF1 and NS. For this new target, an analysis of available drugs will be made to try to identify the best candidate/s which could be explored for in vitro or in vivo testing or as a proof-of-concept. Combining the capabilities of bioinformatic analysis and chemical analysis, a more informed drug choice for screening and/or preclinical testing can be done on the basis of detailed information on drugs and interconnections of targets/pathways. This approach, taking into account the various aspects of a particular model or disease, will attempt to accelerate research by allowing the selection of the most suitable compounds for a particular experiment, allowing for more informed choices.
Citation Format: Salvatore La Rosa, Pamela Knight, Patrice Pancza, Kimberly Scobie, Annette Bakker. Gaps and opportunities for RASopathies: Use of new tools to make the right choice in target and compound selection. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A32. doi: 10.1158/1557-3125.RASONC14-A32
Abstract A42: H-Ras regulates the dynamics of TRAIL death receptors
Authors: Chen Jun-jie , Di Xu , Zhang Yaqin , Bozza William , Zhang Baolin 
Published: May 2015

Abstract
Multiple clinical trials are ongoing to evaluate the potential antitumor activity of recombinant human TNF-related apoptosis inducing ligand (rhTRAIL) and its agonistic antibodies. These protein therapies act through death receptors (DRs) 4 and/or 5 on the cell surface, followed by activation of a caspase cascade and apoptotic cell death. We have previously shown that DR4 and/or DR5 are mislocalized in nucleus and/or cytoplasm in some cancer cells thereby rendering cellular resistance to the targeted therapies. In this study, we have found a correlation between H-Ras expression and TRAIL resistance in the NCI60 panel of human cancer cell lines. The elevated expression of H-Ras is also generally associated with a deficiency of TRAIL death receptors on cell surface. Blockade of H-Ras activity in TRAIL-resistant cells upregulated the surface expression of both DR4 and DR5 without changing their total protein expressions. Subsequently, the cells were sensitized to apoptosis induction by the targeted therapies. To our knowledge, this is the first evidence that oncogenic H-Ras is involved in the regulation of subcellular localization of TRAIL death receptors. H-Ras, along with other Ras GTPases, is known to stimulate outgrowth of cancer cells. Our data suggest that H-Ras may elicit its oncogenic activity at least partly by blocking cytokine-induced apoptosis of cancer cells. Additional studies are warranted to evaluate the therapeutic potential of combinational therapies to simultaneously target H-Ras and TRAIL receptors.
Citation Format: Jun-jie Chen, Xu Di, Yaqin Zhang, William Bozza, Baolin Zhang. H-Ras regulates the dynamics of TRAIL death receptors. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A42. doi: 10.1158/1557-3125.RASONC14-A42
Abstract A44: Identification of new, biologically relevant, G-quadruplexes formed within the critical promoter of kRAS as promising molecular targets
Authors: Hockings Jennifer , Brooks Tracy Ann 
Published: May 2015

Abstract
kRAS is one of, if not the, most prevalent oncogenic aberrations identified to date, and has been well validated as a therapeutic target. It is either upregulated or mutationally activated in ∼30% of all cancers, including 60-90% of pancreatic cancer, and contributes to malignant transformation, tumorigenicity, and a corresponding poor prognosis. Our therapeutic approach to transcriptionally downregulate kRAS is innovate and promising because we are focused on ablating the oncogenic protein, rather than previously unsuccessful attempts focused on modulating its function. Numerous literature reports validate the downregulation of kRAS expression to as an anti-cancer approach, but there has yet to be a concerted effort in this area, primarily due to lack of a molecular target. This is where our findings are exceptionally pioneering, as we focus on globular higher order DNA (G4) formations within the core kRAS promoter as druggable targets with great promise. G4s occur in G/C-rich DNA and are made up of two or more stacked tetrads, formed by the Hoogsteen hydrogen bonding of four guanines, stabilized by monovalent cations. These G/C-rich regions preferentially cluster around the transcriptional start site throughout the genome peaking within 50 bp of the TSS, which is indicative of their regulatory role. Although not universally true, formation of G4s generally functions to silence transcription or translation and thus represents an attractive molecular target for kRAS. The proximal promoter of kRAS contains three separate putative G4-forming regions: near, mid, and far. We have revealed a previously undescribed within the “mid” region of the proximal kRAS promoter, which contains seven contiguous runs three or more continuous guanines. This region forms biologically functional, transcriptionally silencing, equilibrating G4s. This is in contrast to the previously described “near” G4, which we show to have little to no role in transcriptional regulation. These newly described mid-G4 structures have high potential as molecular targets for drug development.
Citation Format: Jennifer Hockings, Tracy Ann Brooks. Identification of new, biologically relevant, G-quadruplexes formed within the critical promoter of kRAS as promising molecular targets. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A44. doi: 10.1158/1557-3125.RASONC14-A44
Abstract A48: The K-ras let-7 miRNA binding site variant and K-ras mutations in colon cancer
Authors: Dalay Nejat , Yalniz Zubeyde , Gurbuz Orkun 
Published: May 2015

Abstract
The K-ras gene is one of the most commonly mutated genes in cancer. The ras proteins act as functional switches in the activation of the MAPK pathway in a complex signaling network coupling growth factor receptors to the intracellular kinases. Mutations in the K-ras gene lead to the constitutive activation of the protein and consequently of the MAPK pathway. K-ras mutations are early events in colorectal carcinogenesis and are observed in 30-40 % of the colorectal cancers. Mutations mostly occur at codons 12, 13 and 61 of the gene and result in the deregulation of the protein activity. Several studies have shown that patients with K-ras mutations do not benefit from therapies with anti-EGFR monoclonal antibodies.
miRNAs are global regulators of gene expression by binding to the 3'-untranslated region of the target mRNA. Recently, it has been shown that the K-ras gene is regulated at the translational level by binding of the let-7 miRNA. The let-7 family of miRNAs is known to play an important role in several cancer types. A germline SNP at the 3'-UTR of the K-ras gene (rs: 61764370 T-G) has been shown to disrupt binding of the let-7 molecule to K-ras resulting in overexpression of the gene and was found to confer increased susceptibility for distinct cancer types. The let-7 miRNA variant was found to be associated with poor outcome in lunh and head and neck cancers. However, the frequency and association of this variant with other cancer types has not been investigated widely.
In this study we evaluated the frequency of the K-ras gene variant in 145 patients with colon cancer and 85 healthy individuals and its possible association with the K-ras gene mutations. The K-Ras gene variant was analyzed by polymerase chan reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, K-ras gene mutations were investigated by real time-PCR. The results were evaluated using the Chi-square test.
The variant allele of the K-ras gene was observed in 23 patients (15.9%) in the heterozygote form. A single patient was homozygous for the variant allele. The variant allele was detected in 12 % of the control group. K-ras gene mutations were present in 46 (32 %) of the patients. The frequency of the variant allele was 13 % among the patients harboring a K-ras gene mutation. The distribution of the variant allele is in accordance with a report on the US control population and no significant difference was observed between the patients and the controls.
Citation Format: Nejat Dalay, Zubeyde Yalniz, Orkun Gurbuz. The K-ras let-7 miRNA binding site variant and K-ras mutations in colon cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A48. doi: 10.1158/1557-3125.RASONC14-A48
Abstract A49: Biological impact of TIMP-1 relative to KRAS status in lung carcinoma
Authors: Gupta Sampa Ghoshal , Kutiyanawalla Ammar , Lee Byung Rho , Rojiani Amyn M. , Rojiani Mumtaz V. 
Published: May 2015

Abstract
Comprehensive sequence analysis of common human cancers has identified several genes that promote tumorigenesis. KRAS is a commonly mutated oncogene in lung adenocarcinoma, most frequently harboring mutations in codon 12 or 13. Therapeutically targeting of KRAS with small molecules has proven ineffective due to difficulties in disrupting protein/protein interactions that are inherent in its activation and function. Recent work has established that many cancers may have KRAS addiction and are considered KRAS dependent while others do not require KRAS for survival. Previously we have shown that TIMP-1 plays an important role in cell survival in lung adenocarcinoma cells. We have overexpressed TIMP-1 in H2009, a KRAS dependent cell line, which rendered these cells resistant to Staurosporine induced apoptosis, whereas knocking down TIMP-1 in A549 (a KRAS independent lung carcinoma cell line) had the opposite effect. We also noted that TIMP-1 overexpression in H2009 cells made them more angiogenic and aggressive in in vitro assays. H2009 and A549 cell lines also showed significant differences in migration, spheroid formation as well as invasiveness. Although H441 cell line is known to be KRAS dependent, it was not as invasive as H2009. These cell lines also showed differential expression of Vimentin and E-cadherin. These results prompted us to review available data regarding these cell lines, which not only harbored different mutations in the cancer promoting genes, but also differed at the regulatory level and functioned through activated ERK1/2, NFkB and Akt pathways. Analysis with the R2 program (http://hgserver1.amc.nl/cgi-bin/r2/) identified a significant correlation between TIMP-1 and KRAS in breast cancers and lung cancer . Interestingly, high TIMP1 levels have been shown to cause chemoresistance by virtue of its anti-apoptotic activity and KRAS has generally been undruggable. Our current study compares KRAS dependent and independent cell lines in relation to TIMP-1 expression. Modulating TIMP-1 renders these cells either more sensitive or resistant to apoptosis. Clinically, patients with elevated TIMP-1 expression have been shown to have shorter overall survival. This study helps to further dissect these pathways and provides a better understanding of the impact of these mutations in lung carcinoma. Supported in part by a Georgia Research Alliance Distinguished Cancer Scientist Award.
Citation Format: Sampa Ghoshal Gupta, Ammar Kutiyanawalla, Byung Rho Lee, Amyn M. Rojiani, Mumtaz V. Rojiani. Biological impact of TIMP-1 relative to KRAS status in lung carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A49. doi: 10.1158/1557-3125.RASONC14-A49
Abstract A56: Loss of wild-type Kras promotes oncogenic Kras-induced leukemogenesis
Authors: Chang Yuan-I , Damnernsawad Alisa , Kong Guangyao , Liu Yangang , Chang Qiang , Zhang Jing 
Published: May 2015

Abstract
Although the Ras genes have long been established as proto-oncogenes, substantial evidence indicates that wild-type (WT) Ras genes act as tumor suppressors in a few solid tumor models. However, recent study by Shannon group discovers that loss of WT Nras does not further promote oncogenic Nras-induced leukemias (Xu et al., 2013), raising the possibility that the earlier finding of WT Ras genes as tumor suppressors restricts to specific Ras isoform(s) and/or specific cell types. Here, we show that in mouse cell lines established from oncogenic Kras-induced acute T-cell lymphoblastic leukemia/lymphoma (T-ALL), WT Kras expression is absent or significantly downregulated due to deletion or epigenetic silencing of the locus. Moreover, WT Kras allele is deleted in ∼30% of primary KrasG12D T-ALL samples but not in pre-leukemia specimens. Our results are consistent with a recent study that WT KRAS allele is deleted in early-stage progenitor ALL patients with an oncogenic KRAS mutation (Zhang, et al., 2012), suggesting that loss of WT Kras expression is a pathological mechanism contributing to T-ALL progression.
To test our hypothesis, we generated compound mice carrying a conditional KrasG12D allele, a floxed WT Kras allele and the Mx1-Cre allele. In the absence of pIpC induction, the leaky expression of Cre is sufficient to induce both oncogenic KrasG12D activation and WT Kras deletion in ∼50% of HSCs. We find that KrasG12D/- mice have a much shorter life span than KrasG12D/+ mice and display more severe leukemia phenotypes, including splenomegaly, leukocytosis, thrombocytopenia, and increase of monocytic cells in peripheral blood and spleen. Bone marrow transplantation experiment confirms that loss of WT Kras promotes oncogenic Kras-induced leukemias in a cell-autonomous manner. Further studies demonstrate that loss-of-WT Kras attenuates KrasG12D HSC depletion and enhances GM-CSF signaling in KrasG12D hematopoietic stem/progenitor cells (HSPCs). We are continuously working on the underlying mechanisms. Taken together, our study elucidates the cross-talk between WT and oncogenic Kras in leukemogenesis and provides mechanistic insights of the WT Kras function as a tumor suppressor.
Citation Format: Yuan-I Chang, Alisa Damnernsawad, Guangyao Kong, Yangang Liu, Qiang Chang, Jing Zhang. Loss of wild-type Kras promotes oncogenic Kras-induced leukemogenesis. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A56. doi: 10.1158/1557-3125.RASONC14-A56
Abstract B18: FOXM1 transcription factor is required for the initiation of lung tumorigenesis by oncogenic KrasG12D
Authors: Wang I-Ching , Ustiyan Vladimir , Zhang Yufang , Cai Yuqi , Kalin Tanya V. , Kalinichenko Vladimir V. 
Published: May 2015

Abstract
Lung cancer is the leading cause of deaths in cancer patients in the United States and world wide. Identification of new molecular targets is clearly needed to improve therapeutic outcomes of this devastating human disease. Activating mutations in K-Ras oncogene and increased expression of FOXM1 protein are associated with poor prognosis in patients with non-small cell lung cancer. Transgenic expression of activated KrasG12D in mouse respiratory epithelium is sufficient to induce lung adenocarcinomas, however, transcriptional mechanisms regulated by K-Ras during the initiation of lung cancer remain poorly understood. FOXM1 transcription factor, a downstream target of K-Ras, stimulates cellular proliferation during embryogenesis, organ repair and tumor growth, but its role in tumor initiation is unknown. In the present study, we used transgenic mice expressing KrasG12D under control of Sftpc promoter to demonstrate that FOXM1 was induced in type II epithelial cells prior to the formation of lung tumors. Conditional deletion of Foxm1 from KrasG12D-expressing respiratory epithelium prevented the initiation of lung tumors in vivo. The loss of Foxm1 inhibited expression of K-Ras target genes critical for the NF-κB and JNK pathways, including Ikbkb, Nfkb1, Nfkb2, Rela, Jnk1, N-Myc, Pttg1 and Cdkn2a. Transgenic overexpression of activated FOXM1 mutant was sufficient to induce expression of these genes in alveolar type II cells. FOXM1 directly bound to promoter regions of Ikbkb, Nfkb2, N-Myc, Pttg1 and Cdkn2a, indicating that these genes are direct FOXM1 targets. FOXM1 is required for K-Ras-mediated lung tumorigenesis by activating genes critical for the NF-κB and JNK pathways.
Citation Format: I-Ching Wang, Vladimir Ustiyan, Yufang Zhang, Yuqi Cai, Tanya V. Kalin, Vladimir V. Kalinichenko. FOXM1 transcription factor is required for the initiation of lung tumorigenesis by oncogenic KrasG12D. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B18. doi: 10.1158/1557-3125.RASONC14-B18