bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5146: Phosphositeplus® and protein modifications in cancer, a case study: profiling tyrosine phosphorylated sites in AML and CML.
Authors: Hornbeck Peter , Zhang Bin , Murray Beth , Skrzypek Elzbieta , Kornhauser Jon , Latham Vaughan 
Published: August 2014

Abstract
PhosphoSitePlus® (PSP) is an open, comprehensive, manually curated, and interactive resource for studying experimentally observed post-translational modifications, primarily of human and mouse proteins. It encompasses over 250,000 non-redundant modification sites, primarily phosphorylation, ubiquitinylation and acetylation. The results of thousands of mass spec experiments, many from various cancers, are aggregated and available for downloading from PSP. The cancers that are most widely represented in PSP include non-small cell lung cancer (NSCLC), chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), breast cancer (BRC), and gastric (GAC) cancer. In order to determine if the sort of binary data in PSP can be useful in identifying sites that are differentially tyrosine phosphorylated between various cancers, 284 CML and 160 AML datasets were downloaded from PSP and analyzed. Differences in the expression of tyrosine phosphorylation were observed: sites that were elevated in AML included PAG1 Tyr317/359/417, WASP Tyr291, SHP-1 Tyr536, and E-Syt1 Tyr822. Sites that were elevated in CML included Bcr and Abl sites as expected, as well as DYRK1A Tyr145, VASP Tyr39, CD2AP Tyr88, SHIP-2 Tyr986/1135/1162. These meta-analyses demonstrate that PSP provides a rich source of easily accessible data that enables proteomic profiling of multiple cancers. See www.phosposite.org
Supported by NIH R44 CA126080, R43 GM65768, and R44 AA014848
Citation Format: Peter Hornbeck, Bin Zhang, Beth Murray, Elzbieta Skrzypek, Jon Kornhauser, Vaughan Latham. Phosphositeplus® and protein modifications in cancer, a case study: profiling tyrosine phosphorylated sites in AML and CML. [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 5146. doi:10.1158/1538-7445.AM2013-5146
Abstract 5150: What is in control of DNA replication timing.
Authors: Gindin Yevgeniy , Meltzer Paul S. , Bilke Sven 
Published: August 2014

Abstract
The initiation of DNA replication at specific sites in the genome is known to be far from perfect, where known initiation sites may or may not fire in a given single cell during specific cell cycle. At the same time, from larger scale perspective, one finds that the timing of DNA replication is highly orchestrated, where specific regions in the genome are copied at specific, reproducible time points throughout S-phase. In an attempt to reconcile these two somewhat discordant observations, many researchers have assumed that a yet unknown, active regulatory mechanism in the cell is responsible for coordinating replication timing.
Here we present a mechanistic explanation for genome-wide replication timing patterns. Our model is purely stochastic, does not contain any active control components and reproduces existing replication timing data with extreme fidelity (correlation &gt; 0.9, about the same as the correlation between technical replicates of the experiment). The main findings of our work are
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Existence of reproducible genome-wide replication patterns do not logically necessitate existence of a complex, active control system in the cell
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Integrative analysis of recently released ENCODE data identifies semi-local chromatin structure as the main determinant of replication timing
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Plasticity of replication timing across different cell types are a direct consequence of changes in the chromatin structure between the different cell differentiation states
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Replication timing is a “systems” phenomenon emerging from the collective action of many uncoordinated, stochastic replication initiation sites. Replication timing cannot be understood by investigating individual initiation sites: deleting up to 30% of high probability initiation sites does not significantly change replication timing
Citation Format: Yevgeniy Gindin, Paul S. Meltzer, Sven Bilke. What is in control of DNA replication timing. [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 5150. doi:10.1158/1538-7445.AM2013-5150
Abstract 5166: Membrane phospholipid asymmetry mediates the selective packaging of protein factors in cancer microparticles.
Authors: Hou Songwang , Williams Carol , Zhao Ming 
Published: August 2014

Abstract
Objective: Growing evidence indicates that cancer cell-derived microparticles (MPs) play important regulatory roles on cellular and system levels. These activities are attributed to protein factors inside MPs. It has been known that contents in MPs are not a passive representation of the host cell, but a collection of factors packaged in a selective fashion. In the current study, we hypothesize that membrane phospholipid dynamics promotes the selective packaging of protein factors by modulating the electrostatic density inside MPs.
Methods: The dynamics of phospholipid species across the membrane bilayer, including phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositides (PIs) are characterized using specific molecular probes. We used exogenous probes, Duramycin and bovine lactadherin, to stain the presence of PE and PS, respectively, on the outer surface of MP membrane. Endogenously expressed probes include GFP-tagged C2 domain of lactadherin (LacC2-GFP), and GFP-tagged 2PH-PLCdelta, are used to assess the relative density of PS and PI, respectively, in the inner leaflet of MP membranes. We examined the distribution of small Rho GTPases, including RhoA, Cdc42 and Rac1, using GFP-labeled reporters. To further examine the electrostatic interactions, we used RhoA mutants with the polybasic amino acids mutated to Gln. Additionally, we constructed a GFP-PBR to validate the electrostatic-dependent packaging mechanism.
Results: PE is externalized to the outer surface of MPs. This is correlated with a greater density of negatively charged phospholipids, particularly PS, in the inner leaflet. The process is independent of apoptosis or the generation of apoptotic bodies. The redistribution of PE to the MP surface is correlated with an elevated presence of small GTPases in a PBR-dependent manner. Mutation of PBR abolished RhoA uptake in MPs. The incorporation of PBR to GFP significantly enhanced GFP localization in MPs. Conclusion: PE externalization to MP surface likely results in a greater density of negatively charged phospholipids, including PS, and to a lesser extent, PIs. An elevated density of anionic phospholipids provides an electrostatic attraction for membrane-associated proteins to MPs. This may provide a general mechanism for the selective sequestration of signal transduction factors in cancer cell-derived MPs.
Citation Format: Songwang Hou, Carol Williams, Ming Zhao. Membrane phospholipid asymmetry mediates the selective packaging of protein factors in cancer microparticles. [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 5166. doi:10.1158/1538-7445.AM2013-5166
Abstract 5175: Survivin Suppression by YM155 involves downregulation of Cyclin Ds and Activation of Rb.
Authors: Shankar Eswar , Corum Sarah L. , Welford Scott M. , Danielpour David 
Published: August 2014

Abstract
The pro-metastatic and survival protein Survivin is robustly overexpressed in carcinomas compared to normal or benign tissue. The imadazolium based small molecule YM155, which was discovered in a chemical library screen of compounds that effectively suppressed the Survivin promoter, induces apoptosis of castration-resistant prostate cancer (CRPC) cells. Despite the current use of YM155 in phase II clinical trials, the mechanisms by which YM155 inhibits the expression of Survivin and kills cancer cells remain unclear. Our laboratory previously reported that the pocket proteins (Rb, p107, p130) suppress Survivin expression by recruiting E2F4 to CDE/CHR promoter elements of the Survivin promoter. Here we studied early signaling responses in a panel of prostate and kidney cancer cell lines and showed that YM155 rapidly decreases the levels of cyclin Ds and activates Rb, preceding the suppression of Survivin expression. We hypothesize that YM155 down-regulates Survivin expression by activating the pocket proteins and promoting their recruitment along with E2F4 to the proximal region of the Survivin promoter. In addition, we provide evidence that the induction of apoptosis by YM155 may be mediated not only by the downregulation of Survivin but also through induced expression of the proapoptotic protein Bim, repression of the anti-apoptotic protein Mcl-1, followed by activation of caspases.
Citation Format: Eswar Shankar, Sarah L. Corum, Scott M. Welford, David Danielpour. Survivin Suppression by YM155 involves downregulation of Cyclin Ds and Activation of Rb. [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 5175. doi:10.1158/1538-7445.AM2013-5175
Abstract 518: Kisspeptin stimulates invasiveness of ERα -negative human mammary epithelial and breast cancer cells.
Authors: Bhattacharya Moshmi M. , Cvetkovic Dragana , Dragan Magdalena , Leong Hon Sing , Babwah Andy 
Published: August 2014

Abstract
Recently, we have shown that KP-10 stimulates invasion of estrogen receptor (ERα)-negative breast cancer cells via transactivation of the epidermal growth factor receptor (EGFR) [Zajac et al. (2011) PLoS ONE 6(6): e21599]. Here we report that KP-10 stimulated cell motility and invasiveness of ERα-negative non-malignant mammary epithelial MCF10A cells that endogenously expressing KISS1R, and MCF10A cells stably expressing KISS1R using three-dimensional (3D) Matrigel cultures. Additionally, exogenous expression of KISS1R in ERα-negative SKBR3 breast cancer cells stimulated invasion in 3D cultures and induced extravasation in vivo using chorioallantoic membrane (CAM) assays. Exogenous KISS1R expression in MCF10A and SKBR3 cells also induced a partial epithelial-to-mesenchymal transition like phenotype as evidenced by the acquisition of a spindle-shaped morphology, intracellular localization of the epithelial marker E-cadherin, increased stress fibre formation and elevated levels of the mesenchymal markers, Snail/Slug, vimentin and N-cadherin. In contrast, KP-10 had no effect on migration and invasion of the ERα-positive T47D and MCF7 breast cancer cells and failed to transactivate EGFR in the ERα-positive cells. This suggested that ERα negatively regulates KISS1R-dependent breast cancer cell migration, invasion and EGFR transactivation. In support of this, we found KP-10-stimulated cell migration, invasion and EGFR transactivation were ablated upon stably expressing ERα in the ERα-negative MDA-MB-231 cells. Lastly, we found that KISS1R was localized at the leading edge of motile cells, where it co-localized with the actin scaffolding protein, IQGAP1. We have identified IQGAP1 as a novel binding partner of KISS1R and have demonstrated that KISS1R regulates EGFR transactivation in breast cancer cells in an IQGAP1-dependent manner. Overall, our data strongly suggest that the ERα status of mammary cells will dictate whether the KISS1R signaling pathway may be a novel clinical target for the treatment of breast cancer metastasis.
Citation Format: Moshmi M. Bhattacharya, Dragana Cvetkovic, Magdalena Dragan, Hon Sing Leong, Andy Babwah. Kisspeptin stimulates invasiveness of ERα -negative human mammary epithelial and breast cancer 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 518. doi:10.1158/1538-7445.AM2013-518
Abstract 5180: Activation of NF- KB by Notch4/Int3 is Rbpj-independant.
Authors: Raafat Ahmed M. , Bargo Sharon , Callahan Robert 
Published: August 2014

Abstract
Transgenic mice expressing the Notch 4 intracellular domain (ICD) (Int3) in the mammary gland have two phenotypes exhibited with 100% penetrance: arrest of mammary alveolar/lobular development and mammary tumorigenesis. Notch4 signaling is mediated primarily through the interaction of Int3 with the transcription repressor/activator Rbpj. Interestingly, Rbpj knockout mice (Wap-Cre+/Rbpj-/-/Wap-Int3) have normal mammary gland development also developed mammary tumors with a slightly longer latency than the Wap-Int3 mice. Thus, Notch-induced mammary tumor development is independent of this interaction. Here, we show that Int3 activates NF-κB in HC-11 cells and induces p50 Phosphorylation in absence of Rbpj. Also, Int3 regulates NF-κB in mammary tumors via IKK-mediated pathway. Treatment of Wap-Int3 baring tumors mice with IKK inhibitor resulted in tumors regression. Also, Wap-Int3/p50 knockout mice did not develop mammary tumors. The data indicates that the NF-κB canonical pathway is the Int3-Rbpj independent pathway.
Citation Format: Ahmed M. Raafat, Sharon Bargo, Robert Callahan. Activation of NF- KB by Notch4/Int3 is Rbpj-independant. [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 5180. doi:10.1158/1538-7445.AM2013-5180
Abstract 5185: RNAi screen identifies a synthetic lethal interaction between Pim1 overexpression and Plk1 inhibition.
Authors: Abdulkadir Sarki , Meer Riet Vander , Roh Meejeon 
Published: August 2014

Abstract
PIM1 kinase is overexpressed in many tumor types including lymphomas and prostate cancer, where it is known to cooperate with the MYC oncogene in promoting tumorigenicity. PIM1 enhances MYC stability and transcriptional activity. Knowledge of the vulnerabilities of Pim1-expressing tumor cells will be of great value in efforts to develop novel anti-cancer therapeutics. Here we have used RNAi screening to identify genes whose depletion is detrimental to Pim1-overexpressing cells. We screened a collection of 570 siRNAs targeting cell cycle, apoptosis, serine-threonine kinase and tyrosine kinase genes for their effects on the viability of Pim1-expressing RWPE1 prostate epithelial cells. We identified the mitotic regulator polo-like kinase (PLK1) as a gene whose depletion is particularly detrimental to the viability of Pim1-expressing prostate cancer cells in vitro and in vivo. Inhibition of PLK1 by shRNA or by the chemical inhibitor BI2536 in prostate cancer xenograft model resulted in a dramatic inhibition of tumor progression in Pim1-overexpressing cells. Interestingly Pim1-overexpressing cells are more prone to mitotic arrest followed by apoptosis. Furthermore, inhibition of Plk1 activity led to the reduction of MYC protein levels both in vitro and in vivo. These results suggest that PLK1 inhibition may be particularly effective against PIM1-expressing tumors due, at least in part, to the fact that PLK1 inhibition reduces MYC protein levels.
Citation Format: Sarki Abdulkadir, Riet Vander Meer, Meejeon Roh. RNAi screen identifies a synthetic lethal interaction between Pim1 overexpression and Plk1 inhibition. [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 5185. doi:10.1158/1538-7445.AM2013-5185
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5191: Gab2 phosphorylation by RSK inhibits Shp2 recruitment and cell motility.
Authors: Zhang Xiaocui , Lavoie Geneviève , Fort Loic , Huttlin Edward L. , Tcherkezian Joseph , Galan Jacob A. , Gu Haihua , Gygi Steven P. , Carreno Sebastien , Roux Philippe P. 
Published: August 2014

Abstract
The scaffolding adapter protein Gab2 (Grb2-associated binder) participates in the signaling response evoked by various growth factors and cytokines. Gab2 is overexpressed in several human malignancies, including breast cancer, and was shown to promote mammary epithelial cell migration. The role of Gab2 in the activation of different signaling pathways is well documented, but less is known regarding the feedback mechanisms responsible for its inactivation. We now demonstrate that activation of the Ras/mitogen-activated protein kinase (MAPK) pathway promotes Gab2 phosphorylation on basic consensus motifs. More specifically, we show that RSK (p90 ribosomal S6 kinase) phosphorylates Gab2 on three conserved residues, both in vivo and in vitro. Mutation of these phosphorylation sites does not alter Gab2 binding to Grb2, but instead, we show that Gab2 phosphorylation inhibits the recruitment of the tyrosine phosphatase Shp2 in response to growth factors. Expression of an unphosphorylatable Gab2 mutant in mammary epithelial cells promotes an invasive-like phenotype and increases cell motility. Taken together, these results suggest that RSK is part of a negative feedback loop that restricts Gab2-dependent epithelial cell motility. Based on the widespread role of Gab2 in receptor signaling, these findings also suggest that RSK plays a regulatory function in diverse receptor systems.
Citation Format: Xiaocui Zhang, Geneviève Lavoie, Loic Fort, Edward L. Huttlin, Joseph Tcherkezian, Jacob A. Galan, Haihua Gu, Steven P. Gygi, Sebastien Carreno, Philippe P. Roux. Gab2 phosphorylation by RSK inhibits Shp2 recruitment and cell motility. [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 5191. doi:10.1158/1538-7445.AM2013-5191
Abstract 5192: MYC amplification and overexpression Is associated With metastasis and drug resistance in a mouse model of anaplastic thyroid carcinoma.
Authors: Russo Marika A. , Di Cristofano Antonio 
Published: August 2014

Abstract
Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to every therapeutic approach. We have generated a mouse model in which simultaneous selective activation of the PI3K pathway and inactivation of p53 in thyroid epithelial cells leads to the development of ATC. These tumors display all the typical features of their human counterpart and metastasize to the lungs in over 25% of cases (20 out of 76).
Recent data have indicated that mammary tumors driven by PI3K activation quickly become resistant to PI3K inhibitors through mechanisms that include Myc amplification. We have used our model to test the hypothesis that Myc overexpression and/or amplification might contribute the aggressive features of PI3K-driven ATC.
Analysis of 46 primary tumors developed by [Pten,p53]thyr-/− mice using a high-sensitivity real-time PCR approach demonstrates that the Myc locus is amplified (copy number ≥4) in about 25% of cases. Conversely, none of 20 metastatic follicular thyroid carcinomas developed by Ptenthyr-/− mice displayed Myc amplification. More strikingly, Myc is amplified in almost 50% (7/15) of ATCs with distant metastases, suggesting that Myc amplification confers more aggressive features to PI3K-driven anaplastic tumors, even in the absence of drug mediated selective pressure.
Furthermore, when injected in syngeneic mice, cell lines established from Myc-amplified tumors grow faster than cell lines derived from tumors without Myc amplification. Myc-amplified cell lines are more resistant than Myc-diploid cells to the PI3K inhibitor BKM120, as well as to paclitaxel and doxorubicin treatment, and this increased resistance can be abrogated by shRNA-mediated Myc downregulation.
These data support a model in which Myc cooperates with PI3K activation to induce more aggressive features, including drug resistance and enhanced metastatic behavior, in advanced thyroid carcinomas.
Furthermore, these data lay the basis for new studies aimed at increasing therapeutic efficacy by interfering with Myc and Myc-dependent pathways.
Citation Format: Marika A. Russo, Antonio Di Cristofano. MYC amplification and overexpression Is associated With metastasis and drug resistance in a mouse model of anaplastic thyroid carcinoma. [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 5192. doi:10.1158/1538-7445.AM2013-5192
Abstract 5203: Identification of an intrinsic determinant critical for maspin subcellular localization and function.
Authors: Dzinic Sijana H. , Kaplun Alexander , Li Xiaohua , Bernardo Margarida M. , Dean Ivory , Lonardo Fulvio , Sheng Shijie 
Published: August 2014

Abstract
Abstract: Maspin is a novel serine protease inhibitor (serpin) that does not act as a classical serine protease inhibitor. Our lab demonstrated that maspin directly inhibits the serine protease-like enzyme, histone deacetylase 1 (HDAC1), which is a major deacetylase up-regulated in many types of cancers. To our knowledge, maspin is the only endogenous polypeptide inhibitor of HDAC1 identified thus far. Interestingly, the differential regulation of maspin during tumor progression is characterized by changes in overall expression and subcellular distribution. In particular, a significant shift in maspin subcellular localization from the nucleus to the cytosol has been observed at the transition from benign epithelial cells to precancerous or low grade carcinoma cells. Accumulated clinical evidence suggests that nuclear retention of maspin is correlated with better overall patient survival. We propose that hypothesized that the configuration and conformation of maspin coded by its primary sequence, i.e. cis elements are the key determinants for where maspin may be retained in a given molecular context. We noted that at the C-terminal end of the RCL sequence is an Aspartate 346 (D346) which is also unique among all maspin homologs and orthologs. In the current study, using the mutagenesis approach, we aimed to determine whether D346 acts as the cis element essential for maspin subcellular localization and function. We showed that in comparison to the maspinWT, which is distributed in both cytosol and nuclei of cancer cells, maspinD346E is predominantly localized in the nuclei of cancer cells. In addition, maspinD346E had an increased affinity towards HDAC1 and it was more effective inhibitor of HDAC1 as compared to the maspinWT. These findings led to a novel molecular model that explains how maspin may be disregulated during tumor progression resulting in loss of its tumor suppressive potential.
Citation Format: Sijana H. Dzinic, Alexander Kaplun, Xiaohua Li, Margarida M. Bernardo, Ivory Dean, Fulvio Lonardo, Shijie Sheng. Identification of an intrinsic determinant critical for maspin subcellular localization and function. [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 5203. doi:10.1158/1538-7445.AM2013-5203