bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5176: PPARγ acetylation governs differentiation function.
Authors: Tian Lifeng , Wang Chenguang , Hagen Fred K. , Casimiro Mathew , Sauve Anthony A. , Pestell Richard G. 
Published: August 2014

Abstract
The peroxisome proliferator-activator receptor gamma (PPARγ) is a member of nuclear receptors (NRs) that plays an important role in the pathogenesis of human diseases, including obesity, type II diabetes and cancer. PPARγ regulates lipid homeostasis by activating the transcription of key genes that are responsible for lipid biosynthesis. NRs undergo post-translational modification including phosphorylation and acetylation. Direct nuclear receptor acetylation by histone acetyltransferases regulates ligand sensitivity and growth properties. Using mass spectrometry and in vivo labeling assays we showed that PPARγ is acetylated in cultured cells. Inhibition of endogenous TSA-sensitive and NAD-dependent deacetylase activity enhanced Pparγ acetylation. SIRT1 bound and deacetylated Pparγ at K154/155. These lysine residues of Pparγ were required for adipocyte differentiation function and determined distinct gene expression signaling pathways. The lysine residues governing sumoylation (K77) and acetylation (K154/155) were shown to have dissociable functions in regulating cell-cycle, gene expression, gene promoter activity, and protein stability. Breast tumor growth, de novo lipid synthesis, induction of autophagy and evasion of apoptosis was promoted by K154/155 and inhibited by K77 in vivo. Pparγ acetylation induced a gene signature that was increased in breast cancer, associated with a reduction in SIRT1 abundance and poor outcome. These studies suggest that the Pparγ lysine motif regulates both ligand-dependent receptor stability and receptor-dependent gene expression and cell functions. Pparγ and SIRT1 signaling converge in vivo to regulate breast tumor lipid metabolism and growth.
Citation Format: Lifeng Tian, Chenguang Wang, Fred K. Hagen, Mathew Casimiro, Anthony A. Sauve, Richard G. Pestell. PPARγ acetylation governs differentiation 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 5176. doi:10.1158/1538-7445.AM2013-5176
Abstract 5177: SIRT2 deacetylates and activates glucose-6-phosphate dehydrogenase (G6PD) to protect cells against oxidative stress.
Authors: Wang Yiping , Zhou Lisha , Zhao Yuzheng , Wang Shiwen , Yang Yi , Ye Dan , Xiong Yue , Guan Kun-Liang 
Published: August 2014

Abstract
Glucose-6-phosphate dehydrogenase (G6PD) catalyzes the first committed step in the pentose phosphate pathway (PPP), which converts β-D-glucose-6-phosphate into D-glucono-1,5-lactone-6-phosphate, while concomitantly producing reducing equivalents in the form of NADPH. NADPH is a required cofactor in reductive biosynthesis,and is also required for the generation of reduced glutathione, the major antioxidant responsible for preventing reactive oxygen species (ROS) damage. Lysine acetylation is an evolutionarily conserved post-translational modification in the regulation of a wide range of cellular processes. Several recent acetylome proteomic studies have identified more than 2000 potential acetylation substrates. Among these identified acetylated proteins is G6PD, implicating a novel modulation of G6PD at the post-translational level. However, our knowledge of how acetylation regulates G6PD activity is limited. This study is directed toward to understand the molecular mechanism by which acetylation regulates G6PD function to regulate cellular redox state in response to oxidative stress. Here, we found that G6PD activity is negatively modulated by acetylation, and the major regulated site of acetylation in G6PD was mapped to K403, an evolutionarily conserved lysine residue. Site-specific genetic incorporation of Nε-acetyl-lysine into the position 403 of G6PD revealed that K403 acetylated G6PD is incapable to form active dimers and displays a complete loss in activity. Moreover, we found that the reversible acetylation of K403 is critical to modulate G6PD activity in response to different physiologic conditions, such as high glucose and oxidizing agents. Cytosolic SIRT2 deacetylated G6PD at K403, and greatly restored G6PD activity by inducing the formation of active dimers. Knockdown of endogenous G6PD led to higher cellular susceptibility to oxidant-induced cell death. Re-expression of wild-type G6PD, but not the acetylated mimic G6PDK403Q, could rescue cells from oxidative injury. Together these results uncover a previously unknown mechanism by which SIRT2 deacetylates and activates G6PD and thus protects cells against ROS damage.
Citation Format: Yiping Wang, Lisha Zhou, Yuzheng Zhao, Shiwen Wang, Yi Yang, Dan Ye, Yue Xiong, Kun-Liang Guan. SIRT2 deacetylates and activates glucose-6-phosphate dehydrogenase (G6PD) to protect cells against oxidative stress. [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 5177. doi:10.1158/1538-7445.AM2013-5177
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5237: Systems level modeling following BRAF inhibition reveals an essential role for Ephrin A2 receptor in therapeutic escape.
Authors: Paraiso Kim H. T. , Fang Bin , Han Dale , Fedorenko Inna , John Jobin , Koomen John , Wargo Jennifer , Flaherty Keith , Meier Friedegund , Smalley Kerian S. M. 
Published: August 2014

Abstract
Although initially striking, the therapeutic efficacy of BRAF inhibition is eventually undermined by adaptive cellular signaling that leads to progressive disease. To date, several mechanisms of BRAF inhibitor resistance have been reported focusing primarily on single alterations. To address how global rewiring of melanoma signaling promotes resistance, we utilized mass spectrometry based phosphoproteomic and network analyses to identify signaling changes in tyrosine, threonine and serine that occur prior to and following acquired BRAF inhibitor resistance. This comprehensive bioinformatics approach uncovered a “resistance interactome” consisting of ∼150 nodes that was marked by significant alterations and the emergence of signaling nodes such as ITGB1, EphA2, EphB4, FAK1, STAT3 and PXN. GeneGo pathway enrichment analysis revealed enhanced cytoskeletal rearrangement, adhesion, integrin signaling, cell migration and extracellular matrix remodeling. Consistent with our bioinformatic predictions, melanoma cell lines with acquired vemurafenib resistance were considerably more invasive than their drug naïve counterparts and showed increased trans-endothelial cell migration. Confirmatory Western blot studies showed increased expression and phosphorylation of EphA2 receptor at Ser897, FAK1 at Ser397 and paxillin at Y118. Knockdown of EphA2 in the resistant cultures inhibited ERK signaling and completely prevented cell invasion and trans-endothelial cell migration. Functionally, EphA2 expression appeared to be regulated by an epigenetic mechanism involving promoter methylation and HDAC1. The clinical relevance of these findings was demonstrated in matched pairs of biopsies from patients receiving either BRAF or BRAF+MEK inhibitors, with significant Ephrin A2 receptor expression being observed in a subset of those on therapy. In summary, chronic MAPK pathway inhibition leads to major remodeling of the melanoma signaling network with EphA2 emerging as a key driver of the resistance phenotype.
Citation Format: Kim H. T. Paraiso, Bin Fang, Dale Han, Inna Fedorenko, Jobin John, John Koomen, Jennifer Wargo, Keith Flaherty, Friedegund Meier, Kerian S. M. Smalley. Systems level modeling following BRAF inhibition reveals an essential role for Ephrin A2 receptor in therapeutic escape. [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 5237. doi:10.1158/1538-7445.AM2013-5237
Abstract 524: Cyclooxygenase pathway in ovarian cancer.
Authors: Rao Gautam G. , Kochel Tyler , Kundu Namita , Reader Jocelyn , Fulton Amy 
Published: August 2014

Abstract
Objectives: To examine the role of the cyclooxygenase (COX) pathway in ovarian cancer. Cyclooxygenases, specifically COX1 and COX2, are frequently overexpressed in malignancies and lead to the synthesis of prostaglandins. A particularly important prostaglandin, PGE2 is exported from the cell into the extracellular milieu by the multi-drug resistance protein 4 (MRP4) transporter where it acts in a paracrine and autocrine manner by activating a family of G-protein coupled receptors (EP1-4). PGE2 is transported into the cell by the prostaglandin transporter (PGT) and catabolized by 15-prostaglandin dehydrogenase (15-PGDH). It has been previously shown that COX1, rather than COX2, is overexpressed in ovarian cancer. Little is known about the role of other members of this pathway, including EP receptors, PGT, MRP4, and 15-PGDH, in this disease.
Methods: HOSE (benign immortalized ovarian epithelial cells) and two ovarian cancer cell lines, SKOV3 and OVCAR3, were grown under standard conditions. Cells were harvested and RNA and protein were isolated. Quantitative RT-PCR was done using the SYBR Green protocol to examine the expression of members of the cyclooxygenase pathway and expressed relative to HOSE cells.
Results: In both ovarian cancer cell lines relative to HOSE, expression of COX2, PGT, EP4, and EP1 was decreased. In SKOV3 cells, COX1 and 15-PGDH expression was decreased but MRP4 levels were comparable to levels detected in HOSE cells. In OVCAR3 cells, COX1 and 15-PGDH expression levels were increased and MRP4 was decreased relative to HOSE cells. PGE2 levels in media will be measured to determine the net effect of these changes. Protein levels of the members of the cyclooxygenase pathway will be determined by western blot.
Conclusions: It is clear that several members of the cyclooxygenase pathway are expressed differently in malignant versus normal ovarian cells. Studies in progress will determine the functional significance of these differences.
Citation Format: Gautam G. Rao, Tyler Kochel, Namita Kundu, Jocelyn Reader, Amy Fulton. Cyclooxygenase pathway in ovarian cancer. [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 524. doi:10.1158/1538-7445.AM2013-524
Abstract 5242: Effect of total saponins of Gynostemma pentaphyllum on melanogenesis and anti-melanoma effect in B16 cells.
Authors: Tsang Ting Fung , Tai William Chi Shing , Hsiao Wendy Wen Luan 
Published: August 2014

Abstract
Melanogenesis is a physiological process of melanin production in response to UV exposure, which is modulated through multi-signaling pathways including cAMP/PKA, Wnt/β-catenin and MAPK signaling cascades. In this study, we investigated both the melanogenesis and anti-melanoma effects of total saponins of Gynostemma pentaphyllum (GpS). Our results showed that non-toxic dosages of GpS stimulated tyrosinase activity and increased melanin content in a dose-dependent manner. Western blot analysis showed that GpS treatment significantly up-regulated the expression levels of the melanogenic proteins, tyrosinase (TYR) and microphthalmia-associated transcription factor (MITF) in a dose-dependent manner. The p-CREB, which is the down-stream target of PKA is also elevated upon GpS treatment. We further observed that H89, a PKA inhibitor, attenuated the GpS induced tyrosinase activity, melanin content, and the protein expression of p-CREB and the nuclear β-catenin. To identify the active saponins, GpS was fractionated in the MCI-CHP 20P column and eluted with methanol in a gradient of 50 to 100% . The resulting ten fractions were tested for their melanogensis activities. We found that Fractions 5 to 9 showed the strongest effect in melanin synthesis in B16 cultures, while up-regulated the expression levels of TYR and MITF, while Fractions 7 to 9 increased nucleus β-catenin protein expression. Further purification of GpS is under way. Our early works showed that GpS exhibits strong anti-cancer effects in both in cellular and animal model. We were wonder whether GpS would exert anti-cancer effect against melanoma. To address this question, we tested and showed that GpS inhibited B16 cells migration in a dose-dependent manner. Meanwhile, GpS also increased G1/S ratio of the GpS-treated B16 cells, suggesting that GpS may act as G1 inhibitor. Our study seems to be in line with the recent reports that stimulation of melanogenesis might be associated with the anti-melanoma effect by decreasing proliferation and invasiveness of melanoma (Chien, et al.,2009). Based on the above results, we proposed that GpS might exert the anti-melanoma effect by stimulating the melanogenesis through the activation of cAMP/PKA and Wnt/β-catenin signaling pathways.
Citation Format: Ting Fung Tsang, William Chi Shing Tai, Wendy Wen Luan Hsiao. Effect of total saponins of Gynostemma pentaphyllum on melanogenesis and anti-melanoma effect in B16 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 5242. doi:10.1158/1538-7445.AM2013-5242
Abstract 5258: PTEN levels are controlled by a nuclear transport receptor in lung cancer.
Authors: Chen Muhan , Herzka Tali M. , Zeeman Martha E. , Plafker Kendra S. , Minderer Matthias , Castillo-Martin Mireia , Cordon-Cardo Carlos , Plafker Scott M. , Trotman Lloyd C. 
Published: August 2014

Abstract
The maintenance of PTEN protein levels is critical for tumor suppression. Yet, the ubiquitination system has been shown to affect PTEN levels both adversely through degradation, as well as positively through nuclear import, and it has remained unclear how these two processes are integrated to prevent cancer. Here we show, that a nuclear import receptor is at the heart of a failsafe system that maintains PTEN levels by mediating its nuclear transport. Loss of import receptor function not only leads to cytoplasmic PTEN accumulation but also prompts PTEN degradation through a novel component of the PTEN ubiquitination system.
By testing the consequences of importin loss in vivo, we found that hypomorphic mice developed lung adenocarcinoma, which presented with aberrant cytoplasmic PTEN localization and degradation, as predicted by our in vitro findings. Since the corresponding human locus suffers frequent deletion as well as inactivating mutations in lung cancer, we propose that this import receptor is a novel tumor suppressor that antagonizes PI 3-Kinase signaling in settings with at least one intact PTEN gene.
Citation Format: Muhan Chen, Tali M. Herzka, Martha E. Zeeman, Kendra S. Plafker, Matthias Minderer, Mireia Castillo-Martin, Carlos Cordon-Cardo, Scott M. Plafker, Lloyd C. Trotman. PTEN levels are controlled by a nuclear transport receptor in lung cancer. [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 5258. doi:10.1158/1538-7445.AM2013-5258
Abstract 5259: Ubiquitination and degradation of EGFR mutants by C-terminus hsp70 interacting protein (CHIP) in non-small cell lung cancer (NSCLC).
Authors: Lee Jeong Eun , Jang Kang Won , Cha Hye Rim , Kim Jo-ock , Jung Sung Soo , Park Dong Il , Park Myoung Rin , Chung Chaeuk 
Published: August 2014

Abstract
Several somatic mutations in the kinase domain of the epidermal growth factor receptor (EGFR), including L858R and exon 19 deletions, are predictive markers for EGFR tyrosine kinase inhibitor treating non-small cell lung cancer (NSCLC), especially adenocarcinoma. The mutational activation of EGFR is stabilized by Hsp90. Therefore Hsp90 inhibition may promote ubiquitin-mediated degradation of EGFR mutants. C-terminus hsp70 interacting protein (CHIP) has been shown to negatively regulate Hsp70 and Hsp90 function and to convert Hsp90 complexes from a chaperone function to one that promotes the ubiquitination and degradation of interacting proteins. Here, we report a novel interaction of EGFR mutants with an E3 ubiquitin ligase CHIP, which can ubiquitinate, and destabilize EGFR mutants. In CHO cells expressing either wild-type or mutant EGFR, inhibition of expression of its mutants: L858R, G719S and del L747_E749del, occurred following overexpression with CHIP, whereas diminution of wild-type EGFR was not in CHIP transfected cells. In full-down assay, CHIP especially interacted with G719S and del L747_E749del, but not L858R, and simultaneously induced ubiquitination of its proteins. Similarly, EGFR proteins in NSCLC cell lines harboring EGFR mutations, PC9, were also declined by CHIP mediated ubiquitination and degradation compared with the protein in wild-type cells. In EGFR mutant cell lines, CHIP inhitibited cell proliferation as well as depletion of phosphor-Akt and ERK. These data suggest that CHIP regulates and stabilizes EGFR mutants and that CHIP may be a novel regulator and marker in EGFR-mutants NSCLC. We confirmed these results by tumor xenograft model. Based on above findings, we conclude that CHIP is a new modulator in EGFR mutant pathway in NSCLC.
Citation Format: Jeong Eun Lee, Kang Won Jang, Hye Rim Cha, Jo-ock Kim, Sung Soo Jung, Dong Il Park, Myoung Rin Park, Chaeuk Chung. Ubiquitination and degradation of EGFR mutants by C-terminus hsp70 interacting protein (CHIP) in non-small cell lung cancer (NSCLC). [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 5259. doi:10.1158/1538-7445.AM2013-5259
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5263: Src inhibition enhances BMP receptor antagonists downregulation of Id1 and growth suppression of lung cancer cells with a K-Ras mutation.
Authors: Langenfeld John E. , Langenfeld Elaine 
Published: August 2014

Abstract
The bone morphogenetic protein 2 (BMP2) is aberrantly expressed in 98% of non-small cell lung carcinomas. Our studies show that selective antagonists (DMH1, DMH2, and LDN) of the type I BMP receptors inhibit the proliferation and induce cell death of lung cancer cell lines, which is mediated at least in part by downregulating the expression of Id1 and Id3. The Id proteins are known to regulate essential aspects of tumorigenesis in many carcinomas.
The Src signaling pathway has been shown to increase the expression of Id1 in A549 cells. Src regulation of Id1 is mediated through the BMP pathway. Src binds to pSmad 1/5, which enhances its translocation into the nucleus. Src also mediates activity of response elements on the Id1 promoter that also bind pSmad 1/5. The BMP signaling pathway suppresses Src signaling, suggesting feedback inhibition.
We examined the ability of a BMP receptor antagonist (DMH2) and a Src antagonist (PP2) to regulate Id1 and Id3 expression in three lung cancer cell lines with a K-Ras mutation (A549,H157,H727) and 3 without a K-Ras mutation (H1299,H865,U1752). PP2 caused a reduction in Id1 and/or Id3 in 2 of the 3 cell lines with a K-Ras mutation (A549,H157). PP2 had no effect or increased the expression of Id1 and Id3 in cell lines without a K-Ras mutation. DMH2 decreased expression of Id1 and Id3 and caused growth suppression of all the cell lines. In the A549 cells, the combination of DMH2 and PP2 caused significantly greater reduction in Id1 promoter activity and growth inhibition than either agent alone. Inhibition of BMP signaling caused an increase in the expression of phosphorylated Src, suggesting feedback regulation.
The data suggests that Src inhibition leads to the downregulation of Id expression predominately in lung cancer cells with a K-Ras mutation. Inhibition of BMP signaling with receptor antagonists causes significant downregulation of Id1/Id3 and growth inhibition even in lung cancer cell lines with K-Ras mutations. Inhibition of BMP signaling may activate Src, suggesting that both BMP and Src antagonists are needed to suppress Id expression and inhibit tumor growth.
Citation Format: John E. Langenfeld, Elaine Langenfeld. Src inhibition enhances BMP receptor antagonists downregulation of Id1 and growth suppression of lung cancer cells with a K-Ras mutation. [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 5263. doi:10.1158/1538-7445.AM2013-5263
Abstract 5283: Regulation of tetraspanins CD151 and CD9 by micro-RNA in breast and prostate cancers.
Authors: Bond Danielle R. , Cairns Murray , Ashman Leonie K. , Weidenhofer Judith 
Published: August 2014

Abstract
Rationale: Tetraspanins are involved in modulating various cellular functions related to cancer progression, such as cell-cell adhesion, migration and signalling. The tetraspanin CD151 (pro-metastatic) is typically over-expressed in cancers, whereas CD9 (metastasis suppressor) is generally under-expressed in cancers. Increased CD151 protein expression in breast and prostate cancers significantly correlates with poor patient outcomes, whereas high CD9 protein expression in these cancers is associated with good patient prognosis. However, progress in developing CD151 and CD9 as prognostic biomarkers and therapeutic targets is hampered by a lack of understanding of the mechanisms controlling altered CD151 and CD9 protein expression in cancers.
Objective: miRNAs, which are small non-coding RNAs involved in post-transcriptional control, are known to be dysregulated in breast and prostate cancers. Bioinformatics analysis has identified around 250 miRNA, which are predicted to bind CD151 or CD9, thus we aim to investigate if miRNAs are able to regulate the expression of CD151 and CD9 in vitro using a range of breast and prostate cancer cell lines.
Methods and Results: Using a dual luciferase reporter assay the level of protein expression regulation via CD151 or CD9 3’UTR, where miRNA generally bind their targets, was determined in 13 breast and prostate cell lines. This analysis showed that the amount of targeting of CD151 and CD9 varied across these cell lines indicating a role for miRNA. Analysis of miRNA expression in normal and cancerous cell lines using miRNA expression arrays and qPCR has confirmed that some miRNAs which are predicted to target CD9 such as miR-25 are up-regulated in many prostate and breast cancer cell lines compared to non-tumourigenic cells. Conversely, miRNA were identified with different expression levels that are predicted to target CD151. To determine whether these miRNAs directly regulate CD151 or CD9, a dual luciferase 3’UTR reporter assay encompassing specific miRNA mimics is being used.
Conclusion: Altered miRNA expression is one way in which prostate and breast cancer cells might alter tetraspanin protein expression to allow cancer progression and metastasis.
Citation Format: Danielle R. Bond, Murray Cairns, Leonie K. Ashman, Judith Weidenhofer. Regulation of tetraspanins CD151 and CD9 by micro-RNA in breast and prostate cancers. [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 5283. doi:10.1158/1538-7445.AM2013-5283
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.