bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4275: Production and characterization of ErbB1 (EGFR) associated with nanolipoprotein particles via cell-based and cell-free methods.
Authors: Scharadin Tiffany M. , Takanishi Christina , He Wei , Saldano Matthew , Carraway Kermit L. , Coleman Matthew A. , Henderson Paul T. 
Published: August 2014

Abstract
The four members of the ErbB family of mammalian receptor tyrosine kinases are essential for the development and maintenance of a variety of tissues. Aberrant activation or over-expression of these receptors leads to the progression of epithelial and brain tumors. An understanding of the mechanistic and structural changes that occur to activate the intracellular receptor tyrosine kinase domain via extracellular ligand binding and receptor dimerization is desirable for identifying specific and efficient methods to inhibit signal transduction. Previous methods to study this process achieved low success due to low protein yield, poor water solubility of the membrane protein, and the large size of receptor. We report progress on overcoming these technical hurdles by forming the ErbB family members in nanolipoprotein particles (NLPs), which are ∼20 nm disc-shaped cell membrane analogs. Here we compare an optimized cell-based method with a novel cell-free method to produce NLPs containing the ErbB1 receptor, also called EGFR. The cell-produced ErbB1-NLPs retain kinase activity compared to cell-free produced material with higher yields. However, the cell-free produced receptors have regions of correct folding and can be produced in less than a day. The cell-free produced constructs can be labeled conveniently with unnatural amino acids to enable characterization of dimerization interactions. These two receptor production systems can be utilized synergistically to enable new studies of conformational changes associated with ligand binding or protein mutations, as well as to identify small molecule inhibitors of these receptors.
Citation Format: Tiffany M. Scharadin, Christina Takanishi, Wei He, Matthew Saldano, Kermit L. Carraway, Matthew A. Coleman, Paul T. Henderson. Production and characterization of ErbB1 (EGFR) associated with nanolipoprotein particles via cell-based and cell-free methods. [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 4275. doi:10.1158/1538-7445.AM2013-4275
Abstract 4277: TRAF2 is a key mediator of the EGF-induced signaling pathway.
Authors: Peng Cong , Zhu Feng , Wen Weihong , Yao Ke , Ma Weiya , Bode Ann , Dong Zigang 
Published: August 2014

Abstract
TRAF2 plays a critical role in the mediation of the TNF-R signaling pathway toward activation of NF-κB and JNKs. Here, we reveal a novel function of TRAF2 in the epidermal growth factor (EGF) signaling pathway. Knockdown of TRAF2 blocked EGF-induced AP-1 activity and anchorage-independent cell transformation. We also showed that TRAF2 is required for RSK2 activity through RSK2 ubiquitination and that RSK2 plays a critical role in AP-1 activity mediated through CREB/c-Fos, which regulate anchorage-independent cell transformation.
Citation Format: Cong Peng, Feng Zhu, Weihong Wen, Ke Yao, Weiya Ma, Ann Bode, Zigang Dong. TRAF2 is a key mediator of the EGF-induced signaling pathway. [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 4277. doi:10.1158/1538-7445.AM2013-4277
Abstract 4284: Cadherin-11 function is required for full neoplastic transformation of mouse fibroblasts by v-Src.
Authors: Guy Stephanie , Geletu Mulu , Arulanandam Rozanne , Raptis Leda 
Published: August 2014

Abstract
The signal transducer and activator of transcription-3 (Stat3) is an important signal transducer with a role in cancer etiology. Following activation of a number of growth factor or cytokine receptors or expression of oncogenes such as vSrc, Stat3 is phosphorylated at tyr705, dimerizes and migrates to the nucleus where it activates transcription from a number of genes involved in cell division and survival. We recently discovered a novel pathway of activation of Stat3: Engagement of cadherin-11 (cad11), a cell to cell adhesion protein, known to be involved in metastasis, induces a dramatic increase in the levels of the Rac and Cdc42 small GTPases, and this leads to Stat3 activation. Stat3 in turn, downregulates the p53 antioncogene and upregulates anti-apoptotic genes, thus offering a potent survival signal.
A large number of oncogenes such as vSrc activate the E2F transcription factor family, which induce the expression of genes involved in cell division. However, at the same time E2F is a potent apoptosis inducer, hence the high demand of transformed cells for anti-apoptotic signals. Since cad11 activates Stat3, a potent survival factor, we examined the effect of downregulation of cad11 upon transformation of mouse Balb/c3T3 fibroblasts by vSrc. Forced expression of high levels of activated Src caused a dramatic reduction in cad11 levels. However, intermediate Src levels, which are physiologically relevant, did allow cad11 expression, albeit at lower levels. Cad11 knockdown in these cells through shRNA expression with a retroviral vector caused a dramatic reduction in Stat3 activity and induced apoptosis. That is, the residual amounts of cad11 present are sufficient to activate Stat3 and prevent apoptosis induced by the Src/E2F axis. Taken together, these findings indicate that cad11, despite its presumed structural role, and in addition to its known role in promoting metastasis, is actually also necessary for full neoplastic transformation by the Src oncogene.
Citation Format: Stephanie Guy, Mulu Geletu, Rozanne Arulanandam, Leda Raptis. Cadherin-11 function is required for full neoplastic transformation of mouse fibroblasts by v-Src. [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 4284. doi:10.1158/1538-7445.AM2013-4284
Abstract 4285: Hypoxia-mediated autophagy enhances HGF-induced cancer cell invasion.
Authors: Lee Young H. , Bottaro Donald P. 
Published: August 2014

Abstract
The cellular response to hypoxia is a major influence on the aggressiveness of primary tumors, yet much of how this response mechanism influences other signaling pathways is unknown. The MET proto-oncogene, which encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF), is often overexpressed in cancers and can drive cell proliferation, invasion, and metastasis. Prior studies demonstrate that the Met tyrosine-kinase receptor drives cell invasion and metastasis under hypoxic conditions, and this invasive phenotype is lost if MET expression is inhibited. Hypoxia also has been shown to sensitize Met-activated pathways to drive HGF-induced invasion through as yet undefined a molecular mechanism. The high mortality rate of metastatic cancer makes it crucial to understand the functional integration of these two prevalent drivers of metastasis, hypoxia and Met signaling, and to identify ways to selectively block cancer cell invasiveness. We show that a chemically generated pseudo-hypoxic condition enhanced HGF-mediated invasion in the papillary renal cell (PRC) carcinoma cell lines ACHN and UOK112. Under hypoxic conditions, cells generated high levels of ROS, which in turn sensitized the mitogen-activated protein kinase (MAPK) pathway to enhance HGF-driven invasion. Furthermore, hypoxic cells displayed increased autophagy as determined by punctate staining of LC3 II using immunocytochemistry and cleaved LC3 immunoblotting. Inhibition of autophagy decreased cell invasion and hypoxia-mediated autophagy was dependent on MAPK pathway activation. These data suggest that hypoxia promotes the invasiveness of PRC-derived cells by increasing ROS-mediated autophagy to sensitize the MAPK pathway to HGF stimulation. Identifying the specific effectors responsible for the integration these signals will improve our understanding of pro-metastatic invasiveness and potentially identify novels targets for its selective blockade.
Citation Format: Young H. Lee, Donald P. Bottaro. Hypoxia-mediated autophagy enhances HGF-induced cancer cell invasion. [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 4285. doi:10.1158/1538-7445.AM2013-4285
Abstract 4294: Copper is required for oncogenic BRAF signaling and tumorigenesis.
Authors: Brady Donita C. , Crowe Matthew S. , Turski Michelle L. , Thiele Dennis J. , Counter Christopher M. 
Published: August 2014

Abstract
The BRAF serine/threonine kinase is mutated, typically at V600, to remain in the active oncogenic state in a large fraction of melanoma, thyroid cancers, and hairy cell leukemia, and to a lesser extent in a wide spectrum of other cancers, thereby activating the kinases MEK1 and MEK2 to stimulate the MAPK pathway and promote cancer. Excitingly, ATP inhibitors of oncogenic BRAF and MEK provide a survival advantage in metastatic melanoma and early clinical studies suggest that coupling BRAF and MEK kinase inhibitors may be even more effective. Thus, the combination of multiple approaches to inhibit MAPK signaling holds great promise for the treatment of BRAF mutation-positive cancers, especially in terms of overcoming resistance. In this regard, we previously found that copper (Cu) influx enhanced MEK1 phosphorylation of its substrates ERK1/2 through a Cu-MEK1 interaction. We show here that genetic loss of the high affinity Cu transporter Ctr1 or mutations in MEK1 that disrupt Cu binding reduced MAPK signaling and oncogenic BRAFV600E-mediated tumorigenesis, which could be rescued by expressing activated ERK2. Importantly, a Cu chelator used in the treatment of Wilson's disease reduced tumor growth of not only BRAFV600E-transformed cells, but also cells resistant to a BRAF inhibitor. Taken together, these results suggest that Cu-chelation therapy could be repurposed for the treatment of BRAFV600E mutation-positive cancers.
Citation Format: Donita C. Brady, Matthew S. Crowe, Michelle L. Turski, Dennis J. Thiele, Christopher M. Counter. Copper is required for oncogenic BRAF signaling and tumorigenesis. [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 4294. doi:10.1158/1538-7445.AM2013-4294
Abstract 4296: High rates of esthesioneuroblastoma in adenomatous polyposis coli (apc) mutant zebrafish suggest a new modifier mutation altering tissue specificity of Wnt/β-catenin-dependent hyperproliferation.
Authors: Greenwood Vivianne E. , Museles Noah , Weinberg Quinn , Glasgow Eric 
Published: August 2014

Abstract
The most common mutation in human colon cancer is inactivation of adenomatous polyposis coli (APC), a key inhibitor of the Wnt/β-catenin pathway. If left untreated, all humans carrying germline APC-inactivating mutations will develop colon cancer by the age of forty. In addition, truncation of APC is the primary contributor to sporadic colon cancer in humans. In zebrafish, the same truncated mutation in apc also causes digestive tract neoplasia. However, the incidence of tumors outside the intestinal system in the apc mutant zebrafish has not been reported. To determine if other tumors arise at high frequencies in the apc mutant, we monitored several cohorts of zebrafish derived from apc(hu147/+) incrosses on a weekly basis over a one-year period, covering the age of 6 to 18 months post-fertilization. Specimens displaying evidence of tumors or general signs of declining health were euthanized, photographed, tail-clipped for genotypic analysis, and then fixed and embedded in paraffin for histological examination. Analysis of the data showed that 1.2% of the apc(hu147/+) zebrafish had abnormally distended abdomens (possibly from intestinal neoplasia), and 1.8% of the mutants developed olfactory neuroblastoma (esthesioneuroblastoma). We have yet to detect a single wild-type fish with esthesioneuroblastoma in these cohorts. Overall, the results indicate that our apc(hu147/+) zebrafish exhibit a remarkably increased incidence of esthesioneuroblastoma compared to wild-type fish or other tumor-prone mutants. Furthermore, relative to the latter, our apc(hu147/+) zebrafish begin developing tumors of any type at an earlier age. Histopathological examination showed these esthesioneuroblastoma tumors to be highly invasive. No previous reports indicate that ethesioneuroblastoma is a common tumor type in apc(hu147/+) zebrafish. Therefore, we propose to have discovered a new modifier mutation, which leads to hyperproliferation of olfactory neuroepithelium in response to dysregulation of the Wnt/β-catenin pathway. Identification of this mutant gene is expected to shed light on interactions of tissue-specific regulators with components of the Wnt/β-catenin signaling pathway to control rates of cell proliferation and differentiation.
Citation Format: Vivianne E. Greenwood, Noah Museles, Quinn Weinberg, Eric Glasgow. High rates of esthesioneuroblastoma in adenomatous polyposis coli (apc) mutant zebrafish suggest a new modifier mutation altering tissue specificity of Wnt/β-catenin-dependent hyperproliferation. [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 4296. doi:10.1158/1538-7445.AM2013-4296
Abstract 430: Inhibition of Pin1 reduces RAD51 expression and enhances radiosensitivity in U87MG glioblastoma cells.
Authors: Chen Edmund I. I. , Ho Chia-Hsin 
Published: August 2014

Abstract
Glioblastoma multiforme (GBM) is the most common primary brain tumor, and has poor prognosis and high recurrences. Pin1, a peptidyl-prolyl isomerase, can recognize phospho-Ser/Thr-Pro motifs and isomerize the cis/trans forms of its substrates. It has been known that Pin1 is involved in cell cycle regulation and cell proliferation, and has affected various protein stability and function, such as cyclin D1 and p53. Recent study has showed that cyclin D1 can directly bind to RAD51 upon radiation in addition to its role in cell cycle. This complex is recruited to DNA damage sites and helps DNA repair. Here, we investigated the role of Pin1 in regulating cyclin D1/RAD51 interaction and affecting the radiosensitivity in U87MG glioblastoma cells. We showed that no interaction was detected between cyclin D1 and RAD51 after ionic radiation in U87MG cells; interestingly, knockdown of Pin1 decreased both cyclin D1 and RAD51 expression and enhanced their sensitivities to radiation. Furthermore, knockdown of Pin1 with IR induced G1 and G2/M arrest which resulted in cell growth inhibition and apoptosis. Importantly, knockdown of Pin1 and combination with radiation yielded increased number of γ -H2AX foci than radiation control cells, suggesting that delayed repair occurred in pin1 knockdown cells. In summary, our results suggest that inhibition of Pin1 decreases RAD51 expression and enhances radiosenstivity in U87MG glioblastoma Cells.
Citation Format: Edmund I. IT Chen, Chia-Hsin Ho. Inhibition of Pin1 reduces RAD51 expression and enhances radiosensitivity in U87MG glioblastoma cells. [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 430. doi:10.1158/1538-7445.AM2013-430
Abstract 4302: TACC3 promotes EMT through the up-regulation of PI3K/Akt and ERK signaling pathways.
Authors: Ha Geun-Hyoung , Park Jong-Sup , Breuer Eun-Kyoung Y. 
Published: August 2014

Abstract
Transforming acidic coiled-coil protein 3 (TACC3) is a member of TACC family, essential for the maintenance of centrosome integrity and the regulation of microtubule assembly and spindle stability during mitosis. In addition to its function in mitosis, TACC3 has been shown to be involved in controlling cell growth, differentiation and transcriptional regulation. Interestingly, deregulated expression of TACC3 has been found in many human cancers, including breast, ovary, bladder, glioblastoma and non-small cell lung cancer. Moreover, our previous microarray analysis suggested that overexpression of TACC3 may be associated with the progression, metastasis and chemoresistance of cervical cancer. Although these findings indicate that TACC3 may play an important role in human cancer, the fundamental molecular mechanisms underlying how TACC3 contributes to cancer initiation, progression and metastasis, and its clinical significance remain elusive. Here, we explored the significance of TACC3 in cervical cancer. Using cervical cancer tissue microarrays, we found that TACC3 is overexpressed in cervical cancer compared with normal cervix. By modulating the expression of TACC3, we found that overexpression of TACC3 leads to changes in cell morphology, proliferation, transforming capability, migratory/invasive behavior as well as the expression of epithelial-mesenchymal transition (EMT)-related markers. Moreover, phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated protein kinases (ERKs) signaling pathways are critical for TACC3-mediated EMT process. Notably, depletion of TACC3 is sufficient to suppress EMT phenotype. Our findings, therefore, identify a novel mechanism that promotes EMT, possibly leading to a more malignant and metastatic tumor phenotype as well as a potential biomarker for diagnosis, prognosis and therapy for cervical cancer.
Citation Format: Geun-Hyoung Ha, Jong-Sup Park, Eun-Kyoung Y. Breuer. TACC3 promotes EMT through the up-regulation of PI3K/Akt and ERK signaling pathways. [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 4302. doi:10.1158/1538-7445.AM2013-4302
Abstract 4313: A LIM protein ajuba suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade.
Authors: Tanaka Ichidai , Osada Hirotaka , Fujii Makiko , Sekido Yoshitaka 
Published: August 2014

Abstract
Malignant mesothelioma (MM) is a highly aggressive neoplasm which is associated with asbestos exposure and around 50% of MM tumors have a mutation of the NF2 tumor suppressor gene. NF2 encodes merlin, a member of the ezrin/radixin/moesin protein family, and merlin is an upstream regulator of the Hippo signaling cascade. Activation of the Hippo pathway induces the activation of serine/threonine kinases LATS1/2, which phosphorylate and inactivate a transcriptional coactivator, YAP. The Hippo pathway activation negatively regulates tissue growth and its inactivation is involved in carcinogenesis.
We previously found that, besides NF2 mutation, a subset of MM tumors harbor LATS2 mutation or YAP oncogene amplification. However, there are yet other MM cases that don't have any of these gene mutations, leading us to hypothesize that other components of this pathway might be altered. Recently, the LIM protein Jub in Droshophila was shown to activate Yoki (ortholog of human YAP) through suppression of the Hippo pathway. To determine whether the human ortholog of Jub, Ajuba, is involved in the Hippo signaling downregulation in MM, we analyzed 20 MM cell lines for the alteration of Ajuba.
We found that the expression of Ajuba was significantly downregulated in 6 of 20 MM cell lines compared to an immortalized normal mesothelial cell line, Met-5A. Interestingly, three of the 6 cell lines with low Ajuba expression showed YAP activation, whereas Met-5A cells showed high Ajuba expression and YAP inactivation, both of which suggested that Ajuba might act as a tumor suppressor instead of oncogenic protein in mesothelial cells. We infected Ajuba-expressing lentivirus into these MM cell lines and found that exogenous Ajuba induced YAP phosphorylation and inhibited MM cell proliferation. Since the CCND1 and connective tissue growth factor (CTGF) genes are well-known transcriptional targets of YAP, we conducted a dual-luciferase reporter assay using these promoter regions to see if Ajuba affects their transcriptional activities. The dual-luciferase assay demonstrated that Ajuba suppressed the promoter activity of these genes and that the suppression of them was attenuated by LATS2 knockdown. These results indicated that Ajuba negatively regulates YAP through activation of LATS2. Our results suggest that the inactivation of Ajuba is one of the mechanisms for constitutive activation of YAP, which results in deregulation of MM cell proliferation.
Citation Format: Ichidai Tanaka, Hirotaka Osada, Makiko Fujii, Yoshitaka Sekido. A LIM protein ajuba suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade. [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 4313. doi:10.1158/1538-7445.AM2013-4313
Abstract 4314: Loss of CYLD promotes cell migration through stabilized ALK5 in human oral squamous cell carcinoma cells.
Authors: Shinriki Satoru , Jono Hirofumi , Li Jian-Dong , Nakamura Takuya , Hayashi Mitsuhiro , Guo Jianying , Shinohara Masanori , Ando Yukio 
Published: August 2014

Abstract
Five-year survival of patients with oral squamous cell carcinoma (OSCC) has not changed apparently for the past 30 years. Although cylindromatosis (CYLD) is thought as a potent tumor suppressor, its biological significances in malignancies are largely unknown. The aim of this study was to clarify the role of CYLD in OSCC progression. We investigated expression of CYLD in OSCC including intraepithelial neoplasia (IEN; n = 48) and invasive carcinomas (n = 133) tissues and normal oral mucosal tissues (n = 35) by immunohistochemistry. In addition, effects of CYLD knockdown by siRNA or its overexpression on OSCC progression using OSCC cell lines. Our immunohistochemical analyses revealed that CYLD expression was significantly reduced at invasive lesions in OSCC tissues whereas it was conserved in normal epithelium and IEN. In addition, lower CYLD expression was associated with poor overall survival in invasive OSCC. Accordingly, CYLD knockdown led to acquisition of mesenchymal state and increased migratory activity in OSCC cells. Interestingly, loss of CYLD enhanced TGFβR1 (ALK5) protein expression by promoting ALK5 stability while overexpression of wild-type CYLD downregulated ALK5. Furthermore, EMT-like changes induced by CYLD knockdown were completely blocked by a TGFβR1 kinase inhibitor in OSCC cells. These findings suggest that downregulation of CYLD promotes invasion through EMT-like changes via ALK5 stabilization in OSCC cells. Further studies for these mechanisms probably provide new insights into the TGFβ signal transduction in cancer and development of a novel therapy in OSCC.
Citation Format: Satoru Shinriki, Hirofumi Jono, Jian-Dong Li, Takuya Nakamura, Mitsuhiro Hayashi, Jianying Guo, Masanori Shinohara, Yukio Ando. Loss of CYLD promotes cell migration through stabilized ALK5 in human oral squamous cell carcinoma cells. [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 4314. doi:10.1158/1538-7445.AM2013-4314