bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3153: The role of ubiquitin in androgen receptor function in prostate cancer
Authors: Darby Steven , Lumsden Hollie , Gaughan Luke , Robson Craig N. 
Published: February 2011

Abstract
IntroductionProstate cancer (PC) is the most common male cancer in the western world. The androgen receptor (AR) plays a central role in PC development and remains the primary target for therapy. Androgen deprivation therapy is currently the standard treatment for PC. However, following a 2-3 year period, a more aggressive cancer usually recurs that is unresponsive to further androgen deprivation and is termed castrate resistant prostate cancer (CRPC). Several AR interacting proteins are components of the ubiquitin-proteasome degradation system, including Mdm2, CHIP and E6AP E3 ligases implicating proteasomal degradation/activation as a key event in AR function. In this study we have investigated which ubiquitin ligases are involved in AR ubiquitination and whether altered ubiquitination levels play a critical role and subsequent AR function in development of CRPC.MethodsIn vitro ubiquitination assays were performed with AR as the substrate with multiple purified E3 ligase enzymes in conjunction with wild type or mutant ubiquitin (K7R, K48 and K63). A panel of E2 conjugating enzymes were also employed to identify which E2/E3 heterodimers were involved in this process. Ubiquitinated AR fragments were gel excised and digested with trypsin. Fragments were then subjected to proteomic analysis to determine the sites of ubiquitination in AR.ResultsIn vitro ubiquitination assays using lysine null ubiquitin (K7R) revealed monoubiquitination of AR in multiple domains of AR in response to four E3 ligases. Screening of an E2 panel also identified multiple E2 conjugating enzymes implicated in AR ubiquitination. K48 ubiquitin (implicated in proteosomal degradation) and K63 ubiquitin (implicated in substrate activation) incorporated into in vitro assays identified differential poly-ubiquitination chain patterns in AR, dependent on which E3 ligase was used in the assay. Proteomic analysis of ubiquitinated AR fragments identified a novel site of ubiquitination within AR.ConclusionsAR was ubiquitinated by four E3 ligases evaluated in this study. Mono- and poly-ubiquitination of AR was identified. Mass spectroscopy revealed a novel site of ubiquitination in AR. Further experiments are being performed, including site directed mutagenesis to determine the importance of the novel ubiquitination site in AR protein proteosomal turnover and transcriptional activation.
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 3153.
Abstract 3154: Translation of TRAF1 is regulated by IRES-dependent mechanism and stimulated by vincristine in lymphoid malignancies
Authors: Yang Lin , Gu Lubing , Li Zhouya , Zhou Muxiang 
Published: February 2011

Abstract
TRAF1 is a member of the TRAF family, which plays important roles in signal transduction that mediate cell life and death in the immune response, inflammatory and malignant diseases. It is known that TRAF1 transcription is inducible by various cytokines, but little is known about the regulation of its protein translation. In the present study, we demonstrated that the human TRAF1 mRNA has an unusually long 5’-UTR that contains an IRES regulating TRAF1 protein translation. By performing gene transfection and reporter assays, we revealed that this IRES sequence is located within the 572 nucleotides upstream from the AUG start codon. An element between nucleotides −392 to −322 was essential for the IRES activity. Interestingly, we found that the TRAF1 expression is induced in cancer cells by chemotherapeutic drug vincristine that regulates cytoplasmic localization of PTB protein, which may contribute to the IRES-dependent translation of TRAF1 during vincristine treatment. These results indicate that TRAF1 translation is initiated via the IRES and regulated by vincristine, and suggest that regulation of the IRES-dependent translation of TRAF1 may be involved in effecting the cancer cell response to vincristine treatment.
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 3154.
Abstract 3166: Inspecting the presence of sialic acid α-2-3- galactose/GalNAC terminal sugar in human stomach adenocarcinoma by lectin histochemistry
Authors: Gohari Minoo 
Published: February 2011

Abstract
Introduction: Glycosilation is the most frequent chemical change related to tumorogenesis which plays an important role in metastatic behavior of tumoral cells. Results of research have shown that changes in terminal sugar of glycoconjugates appear in the process of cancerization. Lectins are specific glycoproteins existing in plant and animal cells which specially attach to terminal sugar of glycoconjugates. This property of lectins make them significant markers in studies relating to histochemistry, biochemistry, recognition and differentiation of cancerous cells. The aim of this study is inspecting the presence of sialic acid α-2-3- galactose/GalNAC terminal sugar in different degrees of differentiation in human stomach adenocarcinoma by using MAA lectin in order to compare the amount of presenting this molecule in different stages and its relation with tumor progression and also for finding useful diagnostic and therapeutic method.
Methods: Tissue samples of 40 stomach adenocarcinoma with different differentiation (well, moderately, poorly and undifferentiated) accompanying with normal tissues were selected from Pathology Department of Imam Reza Hospital in Mashhad, Iran and after studing H&E samples for assuring previous diagnosis, 5micrometer sections were prepared and were stained with MAA/Alcian blue pH 2.5 and then were considered microscopic inspection.
Results: Microscopic study of samples showed no reaction in different degrees of stomach adenocarcinoma that indicates no presentence of sialic acid α-2-3- galactose/GalNAC terminal sugar, and the only positive reaction was between red blood cells of tissue vessels and MAA lectin.
Conclusion: sialic acid α-2-3- galactose/GalNAC terminal sugar is not probably present in adult stomach tissue and is not produced in the changes that result from cancerization of cells, so it probably doesn't have an important and fundamental role in cellular interactions and in making special behaviors that result from neoplasic changes in gastric gland cells.
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 3166.
Abstract 3167: Estrogenic regulation of S6 kinase 1 expression creates a positive feed-forward loop in control of breast cancer cell proliferation
Authors: Holz Marina K. , Seligman Fannie , Spiegel Tirtza , Maruani Denise 
Published: February 2011

Abstract
The 40S ribosomal S6 kinase 1 (S6K1) acts downstream of the mammalian Target of Rapamycin (mTOR), and is sensitive to inhibition by rapamycin. Chromosomal region 17q23 containing the RPS6KB1 gene is frequently amplified in breast cancer cells, and S6K1 is overexpressed in about 30% of cases. Overexpression of S6K1 correlates with increased rapamycin sensitivity. The role of S6K1 in disease development and progression is supported by the observation that S6K1 overexpression is associated with poor prognosis in breast cancer patients. However, the reason for high-level amplification of the RPS6KB1 gene specifically in breast cancer, and not other cancer types is not well understood. We have previously reported that S6K1 regulates growth of breast cancer cells by phosphorylating Estrogen Receptor α (ERα), and co-expression of S6K1 and ERα in breast cancer cells renders them sensitive to combination therapy with rapamycin and tamoxifen. In this study, we demonstrate that in response to estrogen activation, ERα activates expression of S6K1 by upregulating transcription of the RPS6KB1 gene. Increased levels of S6K1 promote further phosphorylation and activation of ERα, creating a positive feed-forward loop. We hypothesize that this relationship promotes breast cancer cell growth, thus providing a selective advantage to S6K1- and ERα-overexpressing cells.
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 3167.
Abstract 318: NAD(P)H: quinone oxidoreductase 1 possesses a strong regulatory role in MAPK signaling pathways
Authors: Patrick Brad A. , Kole Labanyamoy , Jaiswal Anil K. 
Published: February 2011

Abstract
NAD(P)H: quinone oxidoreductase (NQO1) is a cytosolic redox-regulating enzyme modulated by Nrf2-mediated stress signaling pathways, with an established role in regulation of stress-related transcription factors. In these studies we investigate the role of NQO1 in regulation of mitogen-activated protein kinase (MAPK) signaling pathways. Quantitative PCR and western blot studies showed that constitutive levels of several MAPK members are upregulated in NQO1-null mouse skin as well as in skin-derived keratinocytes, relative to wild type. However, though total protein levels are increased, inducibility of these kinases by known MAPK inducers such as EGF and benzo[a]pyrene (BP) is significantly decreased in NQO1-null cells. NQO1 regulation of MAPK signaling was confirmed by studies showing that NQO1 knockdown by siRNA led to decreased MAPK activation, and overexpression of NQO1 protein led to increased MAPK activation by EGF. Similarly, downregulation of activity via dicoumarol caused loss of ERK phosphorylation, while NQO1 activation via t-BHQ caused increased ERK phosphorylation, which was blocked by MAPK pathway-specific inhibitors. To investigate the functional role of MAPK deactivation in skin-derived keratinocytes, studies with BP and menadione showed that lack of NQO1 expression led to increased susceptibility to ROS generation, and that this ROS generation causes increased toxicity. Taken together, these results show a significant role for NQO1 in regulation of MAPK signaling pathways, which ultimately leads to protection against ROS-mediated apoptosis.
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 318.
Abstract 3180: Altered β-catenin phosphorylation pattern in human prostate cancer
Authors: Du Cheng , Zhang Chuanyou , Biswas Md. Helal U. , Balaji K.C. 
Published: February 2011

Abstract
Protein kinase D1 (PKD1) phosphorylates β-catenin at Thr112 and Thr120. The phosphorylation is required for β-catenin membrane trafficking via trans Golgi network (TGN). Data presented in this study indicate that activation of PKD1 shrinks the cytoplasmic pool of β-catenin which mainly is the non-phosphorylation (S33/S37/T41/S45) isoform of β-catenin, suggesting that PKD1 interacts with Wnt/GSK3β signaling pathway. The phosphorylated Thr120 β-catenin (pT120) isoform predominately locates at membrane fraction in cultured prostate cancer cell line C4-2. A newly developed phospho-threonine antibody specifically targeting the pT120 of β-catenin shows accumulation of pT120 β-catenin in TGN in normal prostate tissues. Our study demonstrates that distribution of Thr120 phosphorylated β-catenin is distinct in normal and malignant prostate tissues. In 16/22 (72%) of normal prostate tissues, the pT120 β-catenin is enriched at TGN. In contrast, only 15/200 (7.5%; p &lt; 0.001) of prostate cancer samples had accumulation of pT120 β-catenin in TGN. A vast majority of cancer samples (92.5%) lacking of TGN staining shows the pT120 β-catenin distributed diffusely in cytoplasm, nucleus and plasma membrane. can be more discriminatory compared to conventional β-catenin antibody staining. We propose that β-catenin T120 phosphospecific antibody can be used to study alteration in subcellular distribution of β-catenin and possibly as biomarker in prostate and other tissues, which may facilitate risk stratification or predict disease outcomes.
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 3180.
Abstract 3191: Glypican-5 stimulates rhabdomyosarcoma cell proliferation by activating hedgehog signaling
Authors: Li Fuchuan E. , Shi Wen , Capurro Mariana , Filmus Jorge 
Published: February 2011

Abstract
Glypican-5 is one of the six members of the glypican family. It has been previously reported that glypican-5 stimulates the proliferation of rhabdomyosarcoma cells. In this study we show that this stimulatory activity of glypican-5 is due to its ability to promote Hedgehog signaling. We have previously shown that glypican-3, another member of the glypican family, inhibits Hedgehog signaling by competing with Patched for Hedgehog binding. Furthermore, we showed that glypican-3 binds to Hedgehog through its core protein but not to Patched. Here we demonstrate that glypican-5 can increase the binding of Sonic Hedgehog to Patched. We also show that glypican-5 can bind to both Hedgehog and Patched through its glycosaminoglycan chains. Interestingly, we found that the heparan sulfate chains of glypican-5 display a significantly higher degree of sulfation than those from glypican-3. In addition, we show that glypican-5 interacts with Hedgehog with a lower affinity than glypican-3. Based on these results, we propose that glypican-5 stimulates Hedgehog signaling by facilitating/stabilizing the interaction between Hedgehog and Patched.
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 3191.
Abstract 3202: Imetelstat inhibits telomerase activities in xenograft tumors and bone marrow cells and inhibits tumor growth in xenograft models at plasma exposures equivalent to current clinical exposures in Phase I trials
Authors: Go Ning F. , Villarreal Lyssa , Pattamata Preeti , Nazzal Denise , Lin Tong , Khor Soo-Peang , Delavan-Boorsma Karen , Tressler Robert 
Published: February 2011

Abstract
Telomerase activation is a hallmark of cancer and is critical for dysregulated cell proliferation and cell immortality. Increased telomerase activities were detected in essentially all epithelium derived cancers tested up-to-date and in many hematological malignancies as well, such as multiple myeloma and leukemia. Levels of telomerase activities in the malignant tissues are significantly higher compared to those detected in the normal, regenerating somatic tissues, such as liver and bone marrow cells. Given the differential activation states of telomerase in malignant and normal tissues, telomerase is considered an attractive cancer target by controlling telomere extension and cell immortality. Imetelstat is a first-in-class, lipidated oligonucleotide thio-phosphoramidate telomerase inhibitor. It is a potent and specific telomerase RNA template antagonist, currently in phase I clinical development. Objectives of this study were to demonstrate the in vivo telomerase activity inhibition in xenograft tumors and in bone marrow tissue in animal models, and to correlate the telomerase inhibition effect with mouse plasma drug exposure and xenograft tumor growth inhibition. Our preliminary results showed that treatment with imetelstat at 15-30 mg/kg tiw resulted in plasma concentrations greater than the IC50 for in vitro telomerase inhibition and a plasma exposure level comparable to the tolerable exposure in the clinic. Imetelstat treatment at 15-30 mg/kg tiw for 6 weeks inhibited OVCAR-5 xenograft tumor growth in vivo. Moreover, telomerase inhibition in the xenograft tumors and in the mouse bone marrow was demonstrated. Our results provided evidence of the specific target inhibition by imetelstat treatment in an in vivo system. Our data also suggested a pharmacodynamically efficacious dose level may have been achieved in the clinic.
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 3202.
Abstract 3205: Identification of senescence-inducing microRNAs in normal human epithelial cells
Authors: Shin Ki-Hyuk , Pucar Ana , Kim Reuben , Kang Mo , Park No-Hee 
Published: February 2011

Abstract
MicroRNAs (miRNAs) are novel epigenetic regulators of eukaryotic gene expression and play key roles in many cellular processes. However, the contribution of miRNAs to replicative senescence remains largely unexplored. To understand the role of miRNA in replicative senescence of normal human epithelial cells, we examined the expression profiles of 847 miRNAs in non-senescent (young) and senescent (old) normal human oral keratinocytes (NHOKs). We identified 126 senescence-associated miRNAs (SA-miRs) whose expression was altered greater than 2-fold with senescence. Among SA-miRs, 117 miRNAs (93%) were up-regulated and 9 miRNAs (7%) were down-regulated in senescent NHOKs compared to non-senescent NHOKs. miR-137 and miR-668 were consistently up-regulated with senescence of three independent NHOK cultures and with ionizing irradiation, a premature senescence inducer of NHOKs. Overexpression of miR-137 and miR-668 significantly increased senescence-associated β-galactosidase (SA β-gal) activity and senescence markers, p16INK4A and p53 in non-senescing NHOKs, indicating that they are senescence-inducing miRNAs. Furthermore, we found that these senescence-inducing miRNAs were frequently downregulated in human head and neck squamous cell carcinoma cell lines. Since senescence is considered as a tumor suppressor mechanism, the newly identified senescence-inducing miRNAs need to be considered for therapeutic application for 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 3205.
Abstract 3210: pRb, but not p107 or p130, is required for full induction of p16INK4a in human mammary epithelial cells
Authors: Bazarov Alexey , Korobochkina Irina , Bosire Moses , Hines Curtis , Mukhopadhyay Rituparna , Lee Won Jae , Chicas Agustin , Lowe Scott , Yaswen Paul 
Published: February 2011

Abstract
Pocket family proteins pRb, p107 and p130 are important cell cycle regulators in mammalian cells. In addition to controlling G1 to S transition, they also participate in differentiation and senescence. While all three pocket proteins have similar structures and apparently overlapping functions, defects in only one, pRb, are associated with human cancers. In breast cancer, pRb loss is associated with triple negative (ER-, PR-, HER2-) tumors, which tend to be more aggressive. To explore possible functions of pRb that may be unique, we investigated relative contributions of pocket proteins to cellular senescence initiated by high levels of the cyclin-dependent kinase inhibitor p16INK4a. For this purpose, we silenced pRb, p107 and p130 expression individually with shRNA constructs and exposed MCF7 and MDA-MB-231 breast cancer cell lines to tet-inducible p16. In both malignant lines, knockdown of any single pocket protein was insufficient to prevent p16-induced senescence, indicating the likely existence of compensatory activities of the three pocket proteins in mediating p16-induced senescence. However, our finding that the introduction of HPV E7 - which inactivates all three pocket proteins, prevented p16-induced senescence, is consistent with the hypothesis that as a group, pRb, p107 and p130 constitute essential mediators of p16-induced senescence. To examine the relative contributions of the pocket proteins to cellular senescence initiated by endogenous p16, we used cultured primary human mammary epithelial cells (HMEC) from non-malignant breast tissues. These cells spontaneously induce endogenous p16 and undergo senescence. When we examined the relative contributions of pocket proteins to senescence associated with increased endogenous p16 levels in HMEC, we found that suppressing pRb alone abrogated p16-induced senescence, whereas suppressing p107 or p130 did not. Remarkably, HMEC in which pRb alone was knocked down showed reduced p16 expression and longer proliferative life spans than controls or HMEC in which p107 or p130 were knocked down. These results suggest that pRb, but not p107 or p130, is required for full induction of endogenous p16 in breast cells, and provide a possible explanation for the special tumor-suppressor role of pRb.
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 3210.