bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3136: Activated Src increases total Rac levels and requires Rac and IL6 for full neoplastic transformation
Authors: D'Abreo Carmeline , Arulanandam Rozanne , Geletu Mulu , Raptis Leda H. 
Published: February 2011

Abstract
Activated Src (vSrc) was previously shown to activate Rac through the exchange factors Vav2 and Tiam, and to require Rac for neoplastic transformation, but the exact mechanism remains unclear. Since Src requires the function of the Signal transducer and activator of transcription-3 (Stat3), a Rac target for transformation, we explored the potential role of the Rac/Stat3 axis in transformation by vSrc. In fact, we recently demonstrated a dramatic increase in the activity of Stat3 in breast carcinoma as well as normal epithelial cells and fibroblasts, as a consequence of cell to cell adhesion (Oncogene 23:2600).
In light of these findings, we revisited the question of the role of Rac and Stat3 in vSrc transformation. The results showed that, as previously demonstrated, vSrc expressing mouse fibroblasts had higher Rac activity, at all densities examined. Unexpectedly, our results also demonstrate for the first time a dramatic surge in total Rac upon Src expression, which was at least in part responsible for the Stat3 activity increase. Moreover, Rac activation caused an increase in levels of cytokines of the IL6 family, which was required for Stat3 activation, as shown by the fact that knockdown of gp130, the common receptor subunit of this family, reduced Stat3 activation and neoplastic transformation. Besides transformation, the Rac/IL6/Stat3 axis was required for apoptosis inhibition upon vSrc expression. (supported by CIHR, CBCF-Ontario chapter, US Army breast cancer program, NSERC and Breast Cancer Action Kingston).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3136.
Abstract 3138: Stat3 signaling in thyroid cancer
Authors: Silva Joana , Soares Paula , Trovisco Vitor , Knauf Jeffrey , Fagin James , Bromberg Jacqueline 
Published: February 2011

Abstract
In this study, we addressed the relevance and regulation of Stat3 activation in thyroid cancer. Papillary Thyroid Carcinoma (PTC) comprises almost 80% of thyroid neoplasias and 70% of PTC present activating alterations of components of the ERK-MAPK pathway, either BRAF mutations, RET/PTC rearrangements or RAS mutations. PTCs often display a strong desmoplastic reaction, where tumor is surrounded by a dense stroma and infiltrated with inflammatory cells. To examine the role of Stat3 in thyroid tumours and its putative relation to the associated inflammatory reaction, we analysed Stat3 activation (i.e. Y705-phosphorylation) by IHC in 58 samples of PTC. Approximately 50% of the tumors express pStat3. Frequently, nuclear positivity is only observed in the edge of the tumor as well as in the thyroid cells within tumor stroma. The inner part of the tumor is generally negative. Using multiple cell line models of PTC we observe that both RET/PTC and BRAFV600E expression can lead to Stat3 activation. Similarly, transgenic models of both BRAFV600E and RET/PTC also demonstrate high levels of pStat3 in particular on the inflammatory/leading edge of the tumor. We hypothesize that Stat3 activation, particularly in BRAFV600E tumors, may result from a paracrine effect of stromal cells-derived factors in the adjacent tumor cells. Stat3 is principally activated by autocrine/paracrine IL-6/Jak signaling in lung and breast tumors. Similarly, here we demonstrate that pan-Jak inhibitors block Stat3 activation in PTC cell lines. Furthermore, IL-6 signaling appears to mediate Stat3 activation in RET/PTC, BRAFV600E and RAS expressing cell lines. BRAFV600E knockdown led to a significant decrease of IL-6 levels, as well as of pStat3. In conclusion, we have found that Stat3 is activated in PTC, and that, particularly in BRAFV600E tumors, such activation may result from a paracrine effect of stromal cells through upregulation of IL-6/Jak pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3138.
Abstract 3143: PKD as a downstream target for K-ras in pancreatic cancer
Authors: Storz Peter 
Published: February 2011

Abstract
Growth factor and K-ras-induced generation of reactive oxygen species have important roles in mediating pancreatic ductal adenocarcinoma. Pancreatic cancer cells also express high levels of active transcription factor Nuclear Factor-κB (NF-κB), which is responsible for cell survival and resistance to chemotherapeutics. The serine/threonine kinase Protein Kinase D1 (PKD1) is a sensor for oxidative stress and protects cancer cells by inducing anti-apoptotic and anti-oxidant genes. Here we provide evidence that PKD1 is the means of how high NF-κB activity levels are achieved in pancreatic cancer cells. We also show the contribution of K-ras, which is upregulated in its activity in over 90% of PDAC (pancreatic ductal adenocarcinoma). We found that K-ras in pancreatic ductal HPDE cells increases PKD1 activity and that the depletion of the pancreatic ductal adenocarcinoma cell line Panc-1 from K-ras leads to decreased PKD1 activity and NF-κB activation. As a mechanism we found that K-ras mediates activation of PKD1 via Src and that these signaling events relay to high NF-κB levels. Our data reveal K-ras as an activator of PKD1 and show that both oncogenes, Src and K-ras cooperate to activate NF-κB in PDAC through PKD1. This suggests the K-ras/Src/PKD1/NF-κB pathway as a new potential drug target for pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3143.
Abstract 3144: Tgfbr1 haploinsufficiency inhibits the development of murine mutant Kras-induced pancreatic precancer
Authors: Adrian Kevin , Strouch Matthew , Zeng Qinghua , Barron Morgan , Cheon Eric , Honasage Akilesh , Xu Yanfei , Phukan Sharbani , Sadim Maureen , Bentrem David , Pasche Boris , Grippo Paul 
Published: February 2011

Abstract
Abstract
Transforming Growth Factor Beta (TGFβ) signaling can play dual roles in pancreatic tumor development. In human pancreatic cancer, loss of DPC4/smad4 has been observed in more than half of all pancreatic cancers. In vivo loss of either Smad4 or Tgfbr2 promotes pancreatic adenocarcinoma in mice expressing mutant Kras. Conversely, pharmacologically-induced reduction in Tgfbr1 kinase activity attenuates growth and metastasis of Panc1 cells orthotopically injected into mouse pancreas. To dissect the role of constitutively altered Tgfbr1 signaling in pancreatic cancer development, we crossed Elastase-KrasG12D (EL-Kras) mice with Tgfbr1 haploinsufficient mice to generate EL-Kras/Tgfbr1+/− mice. Mice were euthanized at 6-9 months to compare the incidence, frequency, and size of precancerous lesions in the pancreas. Only 50% of all EL-Kras/Tgfbr1+/− mice developed preinvasive lesions compared to 100% of EL-Kras (wild type Tgfbr1) mice. The frequency of precancerous lesions was 4-fold lower in haploinsufficient than in control mice. The mitotic index of precancerous cells and the observable levels of fibrosis, lipoatrophy, and lymphocytic infiltration were reduced in EL-Kras/Tgfbr1+/− mice. Tgfbr1 haploinsufficiency was demonstrated by decreased levels of psmad2, psmad3, and nuclear localization of psmad4 and was culminated by a reduction in the Tgfbr1: Tgfbr2 ratio in whole mouse pancreas, which was predominantly caused by increased Tgfbr2. Paradoxically, the precancerous lesions of EL-Kras/Tgfbr1+/− mice were considerably larger than those in EL-Kras mice, which was due, in part, to a reduced level of apoptosis. We conclude that Tgfbr1 signaling promotes the development of precancerous lesions in mice. These findings correlate with TGF-β signals that increase ECM deposition and augment immune responses and strongly suggest that Tgfbr1 haploinsufficiency may have a protective role with respect to early pancreatic cancer development. It is also possible that individuals with constitutively decreased TGFBR1 expression may have a decreased risk of pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3144.
Abstract 3149: 4E-BP1 loss of function in pancreatic carcinogenesis
Authors: Azar Rania , Susini Christiane , Bousquet Corinne , Pyronnet Stephane 
Published: February 2011

Abstract
Inactivation of the transcription factor Smad4/DPC4 gene is a frequent event that correlates with aggressiveness of pancreatic adenocarcinomas. We have previously shown that the stress-inducible translational inhibitor 4E-BP1 is a target of Smad4 essential for TGFbeta-mediated inhibition of cell proliferation. Here, we show that 4E-BP1 expression parallels that of Smad4 through the graded stages of pancreatic cancer progression. 4E-BP1 amount transiently increases in human PanIN-1 and PanIN-2 lesions, but is dramatically diminished in PanIN-3 and invasive carcinomas. A similar pattern of 4E-BP1 expression is seen in PanINs from pancreas of mice that carry a pancreas-specific mutated Kras allele (Kras-Pdx1/cre mice). Furthermore, we show in vitro that 4E-BP1 expression is efficiently induced under hypoxia in Smad4+/+, but not in Smad4−/− pancreatic duct cells. We further reveal that, at the molecular level, Smad4 cooperates with HIF1-alpha to induce 4E-BP1 gene transcription in hypoxic cells. Thus, it appears that pancreatic duct cells which carry Smad4 loss are no longer capable of inducing 4E-BP1 under stress conditions. This may have important consequences in pancreatic carcinogenesis as 4E-BP1 is viewed as a stress-inducible factor whose function is to block cellular protein synthesis to concentrate resources on an appropriate stress response aimed at restraining carcinogenesis.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3149.
Abstract 3151: Posttranscriptional regulation of p21 by MCG10, an RNA-binding protein and a target of tumor suppressor p53
Authors: Scoumanne Ariane , Cho Seong Jun , Chen Xinbin 
Published: February 2011

Abstract
The tumor suppressor p53 plays a crucial role in regulating many cellular processes, such as cell cycle arrest, apoptosis, senescence and cell metabolism, in response to stress signals. As a transcription factor, p53 modulates the expression of a plethora of genes, including p21, Killer/DR5, GADD45, TIGAR and MDM2. The tumor suppressor function of p53 is further underscored by the high propensity of p53 mutations found in human cancer. RNA-binding proteins are key modulators in RNA metabolism involved in alternative splicing, mRNA stability, mRNA transport as well as translation. Abnormal expression of RNA-binding proteins is implicated in a growing number of human diseases ranging from neurological disorders to cancer. Here, we showed that MCG10, an RNA-binding protein and a target of p53, regulates the stability of cell cycle inhibitor p21 transcript. Indeed, we found that MCG10 decreases p21 levels induced upon DNA damage. In addition, we showed that MCG10 directly binds to the 3′untranslated region of p21 transcript to destabilize it. Furthermore, we generated MCF7 breast adenocarcinoma and RKO colon carcinoma cell lines in which MCG10 is inducibly knocked down. We found that MCG10 is required for cell proliferation. In addition, we showed that deficiency in MCG10 leads to an increase in basal and DNA damage-induced p21 levels. Taken together, we uncovered a role for RNA-binding protein MCG10 in modulating the p53 pathway through posttranscriptional regulation of p21.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3151.
Abstract 3155: The SCFFBW7 E3 ubiquitin ligase targets Krüppel-like factor 5 (KLF5) for proteolysis in breast cancer
Authors: Zhao Dong , Zheng Han-Qiu , Zhou Zhongmei , Chen Ceshi 
Published: February 2011

Abstract
Krüppel-like factor 5 (KLF5) is an evolutionarily conserved zinc finger-containing transcription factor promoting breast cell proliferation, survival, and tumor growth through upregulating its target gene FGF-BP. The protein abundance of KLF5 has been shown to be strictly regulated at transcriptional and posttranslational levels. Our previous studies suggest that the KLF5 protein degradation is through the ubiquitin proteasome pathway. The WWP1 E3 ligase can target KLF5 for ubiquitin-mediated proteasomal degradation. In this study, we demonstrated the F-box protein FBW7 targets KLF5 for proteolysis and suppresses KLF5's functions in breast cancer. The SCFFBW7 (SKP1-Cullin1-F-box) E3 ligase complex has been shown to target several oncoproteins, including MYC and CyclinE, for proteolysis. FBW7 could be a tumor suppressor due to its frequent mutations in multiple cancers. Here, we first demonstrated that inactivation of endogenous FBW7 by gene knockout, knockdown, or mutation remarkably increases the endogenous KLF5 protein abundances through blocking its degradation in multiple cell lines. Second, we found that overexpression of FBW7 decreases the exogenous and endogenous KLF5 protein levels in HEK293T and SUM149PT cell lines. Functionally, overexpression of FBW7 in the endogenous FBW7 mutated SUM149PT cells decreases the FGF-BP gene expression and the DNA synthesis. Importantly, knockdown of endogenous Fbw7 increases the FGF-BP gene expression, cell proliferation, and survival through upregulating the KLF5 expression in breast cells. These findings suggest that the Fbw7 tumor suppressor inhibit breast cancer cell proliferation and survival at least partially through targeting KLF5 for ubiquitin-mediated degradation. This new regulatory mechanism of KLF5 degradation may result in useful diagnostic and therapeutic targets for breast cancer and other cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3155.
Abstract 3156: eIF4E in human breast cancer and its role in regulating translation of splice variants of breast cancer genes
Authors: Cheung Jenny Yuen-Nei , Wong Ashley San-Yu , Chan Kelvin Yuen-Kwong , Khoo Ui-Soon 
Published: February 2011

Abstract
In eukaryotes, most of mRNAs are translated by the scanning mechanism. The trimeric complex eIF4F (consisting of eukaryotic initiation factor eIF4E, eIF4G and eIF4A) binds to ribosomes and the 5′end of mRNA, unwinding the secondary structures for scanning. eIF4E is the least abundant initiation factor, and may therefore determine the rate of translation. Overexpression of eIF4E can cause malignant transformation of immortalized human cells. Anti-sense oligonucleotides of eIF4E partially reversed the malignant phenotypes, suggesting that overexpression of eIF4E is the direct cause of transformation. Two- to threefold higher eIF4E levels have been detected in breast cancer using immunohistochemistry. Aabout 10% of cellular mRNAs contain atypically long 5’UTR and many of these encode proto-oncogenes and growth factors. It is believed that these long 5’UTR sequences tend to form stable secondary structure, requiring higher levels or activities of eIF4F for their translation.
Over 60% of human genes are alternatively spliced. These may produce variants with different degrees of secondary structure at their 5’-UTR. We hypothesized that the elevated eIF4E level in breast cancer cells allows more effective translation of breast cancer gene variants with extensive 5’UTR secondary structure. These changes in variants profile may be important for breast cancer development and progression. We first analyzed the expression levels of eIF4E in human breast cancer and non-tumor biopsies in tissue microarray. Our preliminary results showed that there was significantly higher eIF4E expression in tumor versus non-tumor and eIF4E expression was positively correlated to estrogen receptor (ER) expression (OR=4.4, p=0.006). Although eIF4E expression levels were independent of tumor grade and size, it was strongly associated with overall clinical ER and progesterone receptor status (OR=6.3, p=0.003 and OR=6.5, p=0.002). The differential translation of breast cancer gene splice variants in breast cancer cell lines is being analyzed and their correlation with the extent of secondary structure of their 5’UTRs will be determined.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3156.
Abstract 3157: Subcellular localization and mRNA targets of a novel human RNA-binding protein, KIAA0020
Authors: Yang Ching-Wen , Cheng Shu-Yu , Chang Christina L. 
Published: February 2011

Abstract
Human KIAA0020 belongs to the PUF family of RNA-binding proteins. Most of family members contain eight RNA-binding Pumilio repeats and are known to regulate mRNA stability and translation. In fact, hunchback, Cyclin B, and HO endonuclease mRNAs are known targets for certain PUF family members in human and other species. Currently little is known about human KIAA0020, which contains six instead of eight Pumilio repeats and shares low homology with its family members. In this study, we characterized this protein and found that wild-type KIAA0020 was localized to multiple foci within the nucleus of HeLa and HEK293T cells. Deletion of C- terminus and, to a less extent, N-terminus of KIAA0020, permitted partial cytosolic localization. Furthermore, we have found a number of mRNA targets that were regulated by KIAA0020 in cells containing ectopic overexpression of KIAA0020 variants or shRNA-mediated knockdown. Based on microarray data analysis from Oncomine, KIAA0020 appears to be deregulated in a variety of human cancer types. Understanding the subcellular localization and mRNA targets of KIAA0020 will improve our knowledge of the function of this protein and its relevance to cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3157.
Abstract 3158: Evidence for a role of EWS in alternative splicing in Ewing's sarcoma
Authors: Riedmann Lucia T. , Kauer Maximilian O. , Jug Gunhild , Kovar Heinrich 
Published: February 2011

Abstract
Ewing's sarcoma family tumors (ESFT) are characterized in 85% of cases by the oncogenic fusion protein EWS-FLI1 resulting from a chromosomal translocation. While FLI1 is an ETS transcription factor, EWS belongs to the evolutionarily conserved FET family of RNA-binding proteins. So far, functional studies of oncogenic EWS fusion proteins have concentrated on their presumed role as transcriptional regulators. However, chimeric FET proteins are usually co-expressed with their intact counterparts and previous protein interaction studies have shown that EWS and EWS-FLI1 interact with each other. Therefore, it is possible that functional interference with normal EWS function accounts for part of the oncogenic activities of EWS-FLI1. However, the role of EWS in post-transcriptional and transcriptional gene regulation is poorly defined. Since FET proteins associate with a number of RNA processing factors, we investigated the influence of modulated EWS expression on genome wide splicing using Affymetrix HuEx-1.0stv2 arrays. For that purpose, we used two model systems: a unique ESFT cell line lacking endogenous EWS was studied upon stable restoration of EWS expression, and an ESFT cell line allowing for inducible RNAi-mediated EWS-FLI1 suppression was analyzed upon transient EWS knockdown. As a result, we found significant differences between cells with and without EWS expression in splicing patterns as well as alternative promoter usage for more than 50 genes. GO analysis of the top ranking genes is consistent with previously suggested functions of the FET protein family such as DNA repair, chromatin structure and RNA transcription. The alternative splicing patterns were verified by RT-qPCR of candidate genes which are currently tested for their functional relevance to ESFT. One of these candidate genes is structural maintainance of chromosome 5 (SMC5). As a core component of the SMC5-SMC6 complex it is involved in sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to DNA double-strand breaks during anaphase. Ongoing studies concentrate on the influence of EWS-FLI1 on EWS-dependent alternative RNA processing patterns in these model systems.
This study is supported by grant P20665-B12 of the Austrian Science Fund FWF
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3158.
Abstract 3160: A redox-sensitive PEST sequence regulates Nrf2 degradation through proteasome pathway
Authors: Ma Quan , Yu Rong 
Published: February 2011

Abstract
Nrf2 transcription factor plays the pivotal role in protection against oxidative stress and chemical carcinogens by inducing a group of antioxidant/detoxification enzymes. Control of Nrf2 degradation is believed to be one of the major mechanisms in regulation of Nrf2-dependent gene expression. Here we report identification of a redox sensitive PEST sequence that targets Nrf2 protein to degradation through proteasome pathway. The PEST sequence locates between amino acids 332 and 359 in human Nrf2. Deletion of this sequence not only prolonged Nrf2 half-life, but also greatly enhanced Nrf2 transactivation function. Insertion of this sequence to the C-terminus of green fluorescence protein (GFP) caused rapid degradation of the fusion protein. Although deletion or insertion of the PEST sequence did not change the status of protein ubiquitination, its dependent protein degradation was sensitive to proteasome inhibition. Interestingly, PEST-mediated protein degradation was also sensitive to oxidant treatments. More over, delivery of a synthetic peptide that mimics PEST sequence caused accumulation of Nrf2 protein and activated downstream genes. Thus, we conclude that, in addition to a previously identified Keap1 pathway, Nrf2 is also actively degraded through a PEST sequence under homeostatic condition. Targeting this sequence would offer a novel approach for activation of Nrf2-dependent protective mechanisms.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3160.