bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2459: The oncogenic activity of MDMx is associated with physical interaction and suppression of retinoblastoma protein
Authors: Xiao Zhi-Xiong , Zhang Haibo , Zhang Yujun 
Published: May 2015

Abstract
The aim of this study is to investigate the role of MDMx (or MDM4) on the regulation of retinoblastoma protein (Rb). Inactivation of Rb plays a critical role in the development of human malignancies. We have previously shown that MDM2, an ubiquitin E3 ligase and a major negative regulator of p53, binds to and promotes proteasome-mediated degradation of Rb independent of p53. MDMX, a homolog of MDM2, also binds to and inhibits p53 transactivation activity, yet it does not possess an ubiquitin E3 ligase activity. In this study, we show that MDMX binds to and promotes proteasome-mediated degradation of Rb in a MDM2-dependent manner. The C-terminal Ring domain of MDMX binds to the Rb C-pocket and enhances MDM2-Rb interaction. Knockdown of MDMX induces Rb protein accumulation, cell cycle G1 arrest, and premature cellular senescence, which can be reverted by simultaneous knockdown of Rb. Furthermore, ablation of MDMX significantly suppresses tumor growth, concomitant with Rb accumulation, in an animal xenograft model. Together, these results demonstrate that MDMX possesses oncogenic activity associated with suppression of Rb and suggest that both MDM2 and MDMX can be targets for cancer therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Zhi-Xiong Xiao, Haibo Zhang, Yujun Zhang. The oncogenic activity of MDMx is associated with physical interaction and suppression of retinoblastoma protein. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2459. doi:10.1158/1538-7445.AM2014-2459
Abstract 2462: Coiled-coil domain 68 (CCDC68) plays a tumor suppressive role in pancreatic adenocarcinoma
Authors: Radulovich Nikolina , Leung Lisa , Ibrahimov Emin , Navab Roya , Sakashita Shingo , Lockwood William , Thu Kelsie , Fedeshyn Yaroslav , Moffat Jason , Lam Wan , Tsao Ming 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is driven by somatic alterations. Recent studies revealed that most genetic alterations are represented by rare mutations in many genes that are either drivers or passengers of PDAC. Using integrative genomics and functional screenings we identified coiled-coil domain 68 (CCDC68) as a putative tumor suppressor (TSG) in PDAC. Combination of Q-RT-PCR and FISH analysis revealed CCDC68 allelic losses in 50% of PDAC cell lines and 44% of primary patient xenografts. 21% of PDAC cell lines and primary patient xenografts also showed decreased levels of CCDC68 mRNA and protein. We also report the discovery of an unstable novel alternate splice variant (SNP rs. 1344011) of CCDC68 expressed by 30% of PDAC patients. Overexpression of full length CCDC68 (CCDC68wt) in PANC-1 and Hs.766T cell lines significantly decreased their cell proliferation, anchorage-independent growth and in vivo tumorigenicity in scid mice. However, the overexpression of novel transcript CCDC68 variant did not affect the cell proliferation or tumorigenicity potential of PANC-1 cells. Finally, we identified that CCDC68 negatively regulates MAPK signalling independently of KRAS status. In conclusion, CCDC68 loss-of-function through copy loss, mRNA downregulation and truncated protein expression suppresses the tumorigenicity of PDAC cell lines suggesting that CCDC68 is a candidate novel TSG in PDAC.
Citation Format: Nikolina Radulovich, Lisa Leung, Emin Ibrahimov, Roya Navab, Shingo Sakashita, William Lockwood, Kelsie Thu, Yaroslav Fedeshyn, Jason Moffat, Wan Lam, Ming Tsao. Coiled-coil domain 68 (CCDC68) plays a tumor suppressive role in pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2462. doi:10.1158/1538-7445.AM2014-2462
Abstract 2464: Angiomotin plays a tumor suppressor role by sequestering oncogenic YAP/TAZ proteins and decreasing amphiregulin secretion in lung cancer
Authors: Kuo Po-Lin , Hung Jen-Yu , Hsu Ya-Ling 
Published: May 2015

Abstract
Lung cancer is the leading cause of cancer death worldwide, with metastasis underlying the majority of lung cancer-related deaths. Angiomotin (AMOT), a scaffold protein, has been shown to interact with oncogenic YAP/TAZ proteins, suggesting its potential role in tumor suppression. However, the functional role of AMOT in lung cancer remains unknown. We observed that the expression of AMOT was significantly decreased in clinical lung cancer specimens. Knockdown of AMOT in a low metastatic CL1-0 lung cancer cell line initiated cancer proliferation, migration, invasion and epithelial-mesenchymal transition. The trigger of cancer progression caused by AMOT loss was transduced by decreasing cytoplasmic sequestration and increasing nuclear translocation of oncogenic co-activators YAP/TAZ, resulting in an increased expression of the growth factor amphiregulin. The tumor promotion by AMOT knockdown was reversed when YAP/TAZ were absent or anti-amphiregulin antibodies were present. Further, AMOT knockdown increased the spread of Lewis lung carcinoma in vivo. Our findings suggest that AMOT is a crucial suppressor of lung cancer metastasis. These observations highlight the critical role of AMOT as a tumor suppressor, and the potential of AMOT as a prognostic biomarker and potential therapy target for lung cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Po-Lin Kuo, Jen-Yu Hung, Ya-Ling Hsu. Angiomotin plays a tumor suppressor role by sequestering oncogenic YAP/TAZ proteins and decreasing amphiregulin secretion in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2464. doi:10.1158/1538-7445.AM2014-2464
Abstract 2467: Connexin43 reduces melanoma growth within a keratinocyte microenvironment and during tumorigenesis in vivo
Authors: Shao Qing C. , Ableser Mark Jake , Penuela Silvia , Laird Dale W. 
Published: May 2015

Abstract
Gap junctions formed from connexins (Cx) have been reported to regulate proliferation, differentiation and apoptosis through formation of intercellular channels between opposing cells. Interestingly, connexins have been identified as tumor suppressors and enhancers, a distinction dependent on the type and stage of disease. In melanomas, the role of connexins during cancer onset and progression remains unclear. In the current study, we hypothesize that expression of Cx26 and Cx43 in BL6 mouse melanomas will increase gap junctional intercellular communication (GJIC) thereby decrease their tumorigenic properties. Western blots, immunofluorescence and dye coupling studies revealed that BL6 cells express low levels of Cx26 , Cx43 and are poorly coupled. When cells were engineered to express Cx26 or Cx43, dye transfer studies revealed that both Cx26- and Cx43-expressing cells were highly coupled. Interestingly, when these connexin-rich melanomas were co-cultured with Cx43-rich keratinocytes, melanoma microtumors remained functionally isolated and failed to couple to surrounding keratinocytes. Growth curve studies revealed that exogenous Cx43, but not Cx26, significantly reduced total cell numbers; that was primarily due to reduced cell proliferation. Furthermore, Cx43 expression significantly reduced anchorage-independent growth compared to controls, however, migration remained unaffected. Additionally, Cx43-expressing melanoma cells displayed a reduction in growth when co-cultured with keratinocytes, despite a lack of heterocellular GJIC. Finally, when grown in in vivo avian embryo model, primary tumor weight was reduced in tumor cells expressing Cx43 , but not in Cx26-expressing melanomas , as compared to controls. Overall, our results would suggest that Cx43 is a potent tumor suppressor in melanomas. Supported by the Canadian Institute of Health Research to DWL.
Citation Format: Qing C. Shao, Mark Jake Ableser, Silvia Penuela, Dale W. Laird. Connexin43 reduces melanoma growth within a keratinocyte microenvironment and during tumorigenesis in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2467. doi:10.1158/1538-7445.AM2014-2467
Abstract 2475: Zpo2 promotes aggressive breast cancer development through downregulation of GATA3
Authors: Shahi Payam , Slorach Euan M. , Chou Jonathan , Lawson Devon , Yu Ying , Werb Zena 
Published: May 2015

Abstract
Metastatic breast cancer is the major cause of poor prognosis and death in women. The transcription factor GATA3 is a key mediator of luminal cell fate determination and homeostasis in adult mammary gland. Loss of GATA3 has been associated with development of metastatic mammary tumors. Here we describe a novel role for transcriptional repressor, Zeppo2 (zinc finger elbow-related proline domain protein2; Zpo2) (ZNF503) in promoting metastatic breast cancer through modulation of GATA3. We demonstrate that Zpo2, through its interaction with repressor of GATA (ROG) is capable of modulating GATA3 transcription in mammary epithelial cells. Overexpression of Zpo2 results in upregulation of EMT associated genes, decreased cell-cell adhesion and increased cellular invasiveness in 3D cultures. Additionally, overexpression of Zpo2 in mammary tumor cells results in enhancement of tumor growth and increased metastasis in orthotopic transplant models. Furthermore, to investigate the importance of Zpo2 in human breast cancer metastasis, we utilized a series of new patient-derived xenograft (PDX) models (primary human xenograft models). The PDX models ranged from poorly metastatic to highly metastatic as was observed in the (affected) original patients. Interestingly, higher Zpo2 expression levels correlate with more aggressive xenograft tumor models. Collectively, our data suggests that Zpo2 plays a potentially significant role in initiating aggressive breast cancer by modulating GATA3 in mammary epithelial cells.
Citation Format: Payam Shahi, Euan M. Slorach, Jonathan Chou, Devon Lawson, Ying Yu, Zena Werb. Zpo2 promotes aggressive breast cancer development through downregulation of GATA3. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2475. doi:10.1158/1538-7445.AM2014-2475
Abstract 2480: Ubiquitination of p53 by Trim39
Authors: Zhang Liguo , Chen Chen , Huang Naijia , Tang Wanli , Kornbluth Sally 
Published: May 2015

Abstract
Trim39 is a RING domain-containing E3 ubiquitin ligase able to directly inhibit the anaphase promoting complex (APC/C). Through analysis of Trim39 function in p53-positive and p53-negative cells we have found, surprisingly, that p53-positive cells lacking Trim39 could not traverse the G1/S transition. This effect did not result from dis-inhibition of the APC/C. Moreover, while Trim39 loss inhibited etoposide-induced apoptosis in p53-negative cells, apoptosis was enhanced by Trim39 knock-down in p53-positive cells. Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. Depletion of Trim39 significantly increased p53 protein levels and cell growth retardation in multiple cell lines. We found that the relative importance of Trim39 and the well-characterized p53-directed E3 ligase, MDM2, varied between cell types. In cells that were relatively insensitive to the MDM2 inhibitor, nutlin-3a, apoptosis could be markedly enhanced by siRNA directed against Trim39. As such, Trim39 may serve as a potential therapeutic target in tumors with wild type p53 when MDM2 inhibition is insufficient to elevate p53 levels and apoptosis.
Citation Format: Liguo Zhang, Chen Chen, Naijia Huang, Wanli Tang, Sally Kornbluth. Ubiquitination of p53 by Trim39. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2480. doi:10.1158/1538-7445.AM2014-2480
Abstract 2482A: ARHI (DIRAS3) downregulates Ras-MAPK signaling and inhibits transformation of NIH3T3 cells through direct interaction with GTP-bound Ras
Authors: Sutton Margie N. 
Published: May 2015

Abstract
Somatic mutation of Ras was the first genetic alteration documented to drive human oncogenesis. Activating mutations of H-Ras, N-Ras, or K-Ras are associated with 30% of all human cancers. Characterization of wild type Ras proteins has identified their essential role in intra-cellular signaling networks controlling cell proliferation, differentiation and survival. Despite intensive efforts, effective targeted therapy directed against mutated Ras has remained elusive. Regulation of Ras function has been studied in depth, but relatively little attention has been paid to physiological inhibitors of Ras. Our group has previously reported that the maternally imprinted Ras-related tumor suppressor gene ARHI (DIRAS3) is downregulated in more than 60% of ovarian cancers and several other tumor types. Re-expression of ARHI at physiologic levels can inhibit ovarian cancer cell proliferation, block migration, induce autophagy, mediate tumor dormancy and block both PI3K and Ras-MAPK signaling. ARHI shares 50-60% homology with the H- and K-Ras genes, differing primarily in a 34-amino acid N-terminal extension that is required for most of ARHI's functions. The mechanism by which ARHI regulates Ras-MAPK signaling is not fully understood. Here, we show that re-expression of ARHI in NIH3T3 murine fibroblasts inhibits cell proliferation, suppresses clonogenic growth and blocks cell transformation by constitutively active mutant H-Ras. Addition of the N-terminal extension of ARHI to mutant H-Ras also prevents malignant transformation. ARHI interacts directly with mutated Ras on co-immunoprecipitation and can inhibit GTP-bound Ras activity following overexpression of the constitutively active construct. We hypothesize that inhibition of the Ras-MAPK signaling pathways following re-expression of ARHI (DIRAS3) may be, in part, the effect of a direct interaction between GTP-bound Ras and ARHI, resulting in the restoration of intrinsic Ras GTPase activity. Our results suggest that ARHI (DIRAS3) may serve as a novel inhibitor of activated Ras, and re-expression of ARHI in tumors exhibiting an oncogenic mutation of Ras might permit more specifically targeted therapy.
Citation Format: Margie N. Sutton. ARHI (DIRAS3) downregulates Ras-MAPK signaling and inhibits transformation of NIH3T3 cells through direct interaction with GTP-bound Ras. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2482A. doi:10.1158/1538-7445.AM2014-2482A
Abstract 2493: Molecular biomarkers for cancer biospecimen integrity
Authors: Agrawal Lokesh , Vaught Jim , Moore Helen 
Published: May 2015

Abstract
Successful implementation of personalized health care requires the availability of biospecimens of sufficient quality to ensure accurate downstream test results, which will in turn determine optimal patient management. Cancer biospecimens of known quality with appropriate clinical annotation are also critical to the process of biomarker discovery and validation that lead to the development of clinical tests. Due to widely varying methods of biospecimen collection, processing, and storage, numerous pre-analytical factors can affect human biospecimen integrity for biomarker research. Such pre-analytical variability can affect the integrity of research biospecimens including plasma/serum and fixed cancer tissues used for biomarker analysis. The National Cancer Institute (NCI) Biorepositories and Biospecimen Research Branch (BBRB) was established to address the scientific and policy issues that affect the procurement of and access to high quality specimens for research. The NCI Biospecimen Research Network (BRN) was established to sponsor and conduct research on biospecimen pre-analytical factors and their affect on molecular integrity, to support the development and adoption of evidence-based standardized biospecimen handling procedures. In this presentation we will summarize BRN-supported studies to identify biomarkers that may be used as sentinel markers of plasma stability using mass spectroscopy proteomics and analysis of circulating miRNA, and the development of intrinsic controls for FFPE tissues. In one of the projects, identification of protein biomarkers using mass-spectrometry and Illumina arrays in plasma led to the development of a biomarker panel for serum/plasma integrity; these biomarkers are currently being validated. A second project studied the effects of pre-analytical variables on circulating miRNA and identified and validated new and improved housekeeping miRNA, as well as novel biomarkers associated with breast cancer. In another study, a series of biomarkers have been validated by construction of tissue microarrays from 93 breast cancer specimens with known time to fixation delays. A tissue quality index (TQI) model was generated to predict the time to fixation and tissue quality by measuring a subset of biomarker proteins in breast cancer tissues using AQUA technology. The progressive efforts taken by BRN investigator-led projects to identify and validate biomarkers for sample integrity will be incorporated into efforts to develop new biospecimen evidence-based practices for clinical biomarker research.
Citation Format: Lokesh Agrawal, Jim Vaught, Helen Moore. Molecular biomarkers for cancer biospecimen integrity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2493. doi:10.1158/1538-7445.AM2014-2493
Abstract 2498: Detection of S-nitrosylated heat shock protein 90 in renal cell cancer
Authors: Hongo Fumiya , Ueda Takashi , Ito-Ueda Saya , Oishi Masakatsu , Nakamura Terukazu , Naya Yoshio , Miki Tsuneharu 
Published: May 2015

Abstract
Purpose: Nitric oxide (NO) is a versatile signaling molecule. Its roles in a variety of physiological functions in mammals are beginning to be understood. It has been demonstrated that NO up-regulates the expression of the Fas receptor on human tumor cells via specific inactivation of transcription repressor YY1 DNA binding activity to the silencer region of the Fas promoter (Hermes G., et al. 2001). We also showed that inactivation of YY1 via protein S-nitrosylated by NO in prostatic cancer could be identified (Hongo F., et al. 2005). This post-translational modification, known as S-nitrosylation, has emerged as a highly conserved and spatiotemporally specific signaling mechanism. The objective of our study was to examine the effect of NO donor treatment on renal cell cancer.
Methods: We examined the effect of the NO donor DETA-NONOate (100-500uM) on the following renal cell cancer cell lines; CAKI-1, NC65, and ACHN. Anti-S-nitroso-Cysteine antibody in the rabbit (SIGMA-ALDRICH) was applied as a primary antibody for immunohistochemistry. The biotin-switch technique was applied to detect specific S-nitrosylated proteins. Whole cell lysates were extracted from ACHN cells employed with DETA-NONOate. Using an S-nitrosylated detection kit (Cayman Chemical Company), S-NO was replaced by Biotin. Cell lysates were incubated at 4 oC with 30 μL of Dynabeads M-280 Streptavidin (Invitrogen) for 3 hrs. After five washes with wash buffer (S-Nitrosylation Wash buffer), the protein complex was eluted from anti-biotin dynabeads by incubation with 1x volume of elution buffer (0.1M glycine (pH2.0)) twice for 15 min. Each sample was added to an SDS-polyacrylamide gel for mass spectrometry.
Results: Significant up-regulation of S-nitrosylated proteins employed with DETA-NONOate was observed by immunohistochemistry. Specific S-nitrosylated proteins in ACHN cells were detected by the biotin-switch technique and included HSP90 (heat shock protein 90), GRP78 (HSP70 family), HSP70, and pyruvate kinase M2. In ACNH cells, Significant up regulation of S-nitrosylated HSP90 by western blot.
Conclusions: Our data showed that NO treatment significantly increased S-nitrosylation of several proteins. S-nitrosylation should be considered as one of the mechanisms by which NO acts on cancer cells.
Citation Format: Fumiya Hongo, Takashi Ueda, Saya Ito-Ueda, Masakatsu Oishi, Terukazu Nakamura, Yoshio Naya, Tsuneharu Miki. Detection of S-nitrosylated heat shock protein 90 in renal cell cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2498. doi:10.1158/1538-7445.AM2014-2498
Abstract 2503: Differential expression of cytoskeletal proteins in acute lymphoblastic leukemia in accordance with initial response to chemotherapy
Authors: Kang Kee R. , Park Eun Sil 
Published: May 2015

Abstract
Precursor B lymphoblastic leukemia is a B-cell lineage neoplasm of lymphoblasts. The initial response to induction-chemotherapy is the most important prognostic factor in acute lymphoblastic leukemia (ALL) patients. Patients with rapid-early-response (RER, below 5% of blast in bone marrow at day-7 after induction-chemotherapy) have better event-free survival compared to slow-early-responders (SER, above 25% of blast). The drug sensitivity/resistance of leukemic blasts is mainly determined by specific genetic abnormalities, however, in more than 20% of ALL, the abnormalities remain unclassified, and the treatment outcome persist variable. This study aimed to find plausible biomarkers of drug sensitivity/resistance in ALL using proteomic analysis. We identified 28 up-regulated and 25 down-regulated proteins in SER_as compared to RER_by MALDI-TOF and mass spectrometry. Of these, 14-3-3 isoforms and cytoskeletal proteins were differentially expressed. Alpha tubulin and 14-3-3 gamma, down-regulated in RER were further verified by Western blot analysis. In further studies, the roles of these proteins in drug sensitivity/resistance are undergoing to elucidate as a potential biomarker for ALL therapy.
Citation Format: Kee R. Kang, Eun Sil Park. Differential expression of cytoskeletal proteins in acute lymphoblastic leukemia in accordance with initial response to chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2503. doi:10.1158/1538-7445.AM2014-2503