bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-111: A stable transcription factor complex nucleated by dimeric AML1-ETO controls leukemogenesis.
Authors: Sun Xiao-Jian , Wang Zhanxin , Wang Lan , Jiang Yanwen , Soong T. David , Kost Nils , Chen Wei-Yi , Elemento Olivier , Fischle Wolfgang , Melnick Ari , Patel Dinshaw J. , Nimer Stephen D. , Roeder Robert G. 
Published: August 2014

Abstract
Transcription factors are frequently altered in leukemia through chromosomal translocation, mutation or aberrant expression. AML1-ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukemia (AML), is a transcription factor implicated in both gene repression and activation. AML1-ETO exists as dimer/oligomer through its NHR2 dimerization domain. Given that the AML1-ETO dimerization has been shown to be critical for its leukemogenic activity, it is important to identify coregulatory factors that “read” the NHR2 dimerization and contribute to leukemogenesis. We now show that, in leukemic cells, AML1-ETO resides in and functions through a stable protein complex (AETFC) that contains several hematopoietic transcription factors and cofactors. These AETFC components stabilize the complex through multivalent interactions, provide multiple DNA-binding domains for diverse target genes, colocalize genome-wide, cooperatively regulate gene expression, and contribute to leukemogenesis. Within the AETFC complex, the AML1-ETO dimerization is required for a specific interaction between the dimerized NHR2 domain and a novel NHR2-binding (N2B) motif in E proteins. Crystallographic study of the NHR2-N2B complex reveals a unique interaction pattern in which an N2B peptide makes direct contact with side chains of two NHR2 domains as a dimer, providing a novel model of how dimeric transcription factors create a new protein-binding interface through dimerization. Intriguingly, disruption of this interaction by point mutations abrogates AML1-ETO-induced hematopoietic stem cell self-renewal and leukemogenesis. These results reveal new mechanisms of action of AML1-ETO in leukemogenesis and provide potential therapeutic possibilities for targeting t(8;21)+ AML.
Citation Format: Xiao-Jian Sun, Zhanxin Wang, Lan Wang, Yanwen Jiang, T. David Soong, Nils Kost, Wei-Yi Chen, Olivier Elemento, Wolfgang Fischle, Ari Melnick, Dinshaw J. Patel, Stephen D. Nimer, Robert G. Roeder. A stable transcription factor complex nucleated by dimeric AML1-ETO controls leukemogenesis. [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 LB-111. doi:10.1158/1538-7445.AM2013-LB-111
Abstract LB-113: Genome-wide mapping of TFE3-fusion target genes.
Authors: Huang Ying , Baba Masaya , Hasumi Hisashi , Hasumi Yukiko , Schmidt Laura , Wakabayashi Yoshi , Zhu Jun , Yang Wenjing , Linehan Marston 
Published: August 2014

Abstract
Xp11.2 translocation renal cell carcinoma (RCC), also known as TFE3-fusion associated RCC, is a recently classified distinct subtype of RCC. It is defined by several different translocations involving chromosome Xp11.2, all resulting in gene fusions involving the Transcription Factor Binding to IGHM Enhancer 3 (TFE3) gene. However, the detailed function of TFE3-fusion proteins in TFE3-fusion associated RCC still remains unknown, and there is no effective treatment for patients with this RCC subtype. In this study we sought to investigate the detailed regulatory network of TFE3-fusion proteins by using doxycycline-inducible HA-tagged TFE3-fusion cell lines and chromatin immunoprecipitation (ChIP)-sequencing. Doxycycline-inducible cell lines that express HA-tagged TFE3-fusion (PRCC-TFE3, PSF-TFE3 and NONO-TFE3) and TFE3 wild-type proteins were established in the HK2 cell line. Genome-wide screening of the binding characteristics of TFE3-fusion proteins and TFE3 wild-type protein in doxycycline-induced cell lines was performed using a chromatin immunoprecipitation sequencing (ChIP-seq) assay. Hierarchical clustering was used to analyze the genes regulated by each type of TFE3-fusion protein compared with TFE3 wild-type protein. The total number of CHIP-seq reads in TFE3 wild-type cell line was 18552874 and enrichment of the promoter region was 1.2. In contrast, the total number of CHIP-seq reads in PRCC-TFE3, PSF-TFE3 and NONO-TFE3 cell lines were 15332969, 20426159 and 17639467, respectively. Enrichment of promoter region in each of the TFE3-fusion cell line was 1.5, 2.4 and 2.2, respectively. There were 80 motifs enriched (Z score &gt;1.5) by expression of PRCC-TFE3 protein compared to TFE3-wild type protein, 104 motifs enriched by PSF-TFE3 protein and 39 motifs by NONO-TFE3 protein expression. Work is ongoing to identify the target genes that are co-regulated in TFE3-fusion cell lines relative to the TFE3 wild-type cell line. Our aim is to identify activated pathways in common among the different TFE3-fusion cell lines compared to the TFE3 wild-type cell line. We anticipate that this study will further our understanding of mechanisms that activate TFE3-fusion proteins facilitating the identification of therapeutic targets for effective treatment of TFE3-fusion associated RCC.
Citation Format: Ying Huang, Masaya Baba, Hisashi Hasumi, Yukiko Hasumi, Laura Schmidt, Yoshi Wakabayashi, Jun Zhu, Wenjing Yang, Marston Linehan. Genome-wide mapping of TFE3-fusion target genes. [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 LB-113. doi:10.1158/1538-7445.AM2013-LB-113
Abstract LB-114: Genome wide analysis reveals a "liability" in the mutant p53 transcriptome.
Authors: Martinez Luis A. , Kollareddy Madhusudhan , Varanasi Lakshman 
Published: August 2014

Abstract
One of the mechanisms by which the oncogene mutant p53 (mtp53) suppresses chemotherapy induced apoptosis is by directly regulating gene expression. We speculated that within the mtp53 transcriptome, there may be transcriptional targets that constitute "liabilities" that can be exploited to kill mtp53 bearing cancer cells. CHIP-Seq analysis of mtp53 revealed that the key enzyme required for activation of nucleoside analogs, deoxycytidine kinase (DCK), is a direct target of mtp53. We demonstrate that mtp53 associates with the promoter of the DCK gene and that knockdown of mtp53 in multiple cancer cell lines results in reduced DCK mRNA and protein levels. Furthermore, we show that mtp53 cooperates with the ETS transcription factors to induce DCK expression. Knockdown of mtp53 or ETS proteins reduces the activity of a DCK promoter-luciferase construct, thus reinforcing that DCK is a transcriptional target of an ETS/mtp53 complex. In contrast, knockdown of wildtype p53 has no effect on the expression of DCK, indicating that the ability of mtp53 to regulate DCK expression is a gain-of-function activity. Based on our findings, we reasoned that by upregulating DCK expression, mtp53 may increase the sensitivity of cancer cells to nucleoside analogs. Indeed, shRNA knockdown of DCK reduces the sensitivity of cancer cells to gemcitabine. Importantly, suppression of mtp53 or ETS proteins also renders cancer cells less sensitive to gemcitabine. Thus, these data support the notion that mtp53 can sensitize cells to nucleoside analogs via DCK. Our data reveal the presence of a transcriptional "liability" in the mtp53 transcriptome that may help predict which patients will have a better therapeutic response to nucleoside analogs.
Citation Format: Luis A. Martinez, Madhusudhan Kollareddy, Lakshman Varanasi. Genome wide analysis reveals a "liability" in the mutant p53 transcriptome. [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 LB-114. doi:10.1158/1538-7445.AM2013-LB-114
Abstract LB-117: Myc phosphorylation suppresses transformation through novel regulatory regions.
Authors: Dingar Dharmendra , Wasylishen Amanda R. , Chan-Seng-Yue Michelle , Huang Ling , Bros Christina , Tu William , Meyer Natalie , Boutros Paul C. , Penn Linda Z. 
Published: August 2014

Abstract
Myc is a proto-oncogenic transcription factor, whose expression is deregulated in numerous human tumours and over-expression in animal models can cause tumorigenesis. Myc is important in cancer initiation and progression and therefore to develop successful approaches targeting Myc, a better understanding of both the mechanisms of Myc regulation and subsequent deregulation in cancer is important. Identification of Myc post-translational modifications (PTMs) that are essential for its oncogenic activity remains largely unknown. Therefore, detecting those key PTMs and there effect on gene expression would shed more light on the mechanisms of Myc dependent tumorigenesis. In our study, we screened a panel of Myc phosphorylation mutants in MCF10A cells for their ability to promote anchorage-independent colony growth and we identified two previously uncharacterized mutants that increased Myc-dependent transformation: S71A/S81A and 340Cl-A (T343A, S344A, S347A, and S348A). We further confirmed that gain-of-function serine and threonine mutants potentiated transformation in SH-EP neuroblastoma cells and three-dimensional MCF10A acini. Additionally, to investigate the mechanism of increased transformation and mutants' selectivity for gene transcription, we conducted genome-wide mRNA expression analysis of MCF10A acini and identified 112 genes regulated by all MYC alleles, and 158 genes regulated by all three transforming phosphorylation mutants but not wild-type MYC. We performed genome-wide ChIP in MCF10A cells, integrated this with gene transcription data, and showed that the majority of genes with altered expression also have MYC binding in their promoter regions, further suggesting that these gene expression changes are directly regulated by Myc. In conclusion, phosphorylation of S71/S81 and 340Cl amino acid residues negatively regulates Myc dependent transformation, suggesting that better understanding of Myc regulation through the phosphorylation of these residues may provide opportunities to therapeutically target Myc.
Citation Format: Dharmendra Dingar, Amanda R. Wasylishen, Michelle Chan-Seng-Yue, Ling Huang, Christina Bros, William Tu, Natalie Meyer, Paul C. Boutros, Linda Z. Penn. Myc phosphorylation suppresses transformation through novel regulatory regions. [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 LB-117. doi:10.1158/1538-7445.AM2013-LB-117
Abstract LB-127: HTLV-1 Tax inflicts severe DNA damage through the activation of nitric oxide production: A credible pathway for transformation of HTLV-1 infected cells.
Authors: Baydoun Hicham , Ratner Lee 
Published: August 2014

Abstract
Adult T-cell Leukemia-Lymphoma (ATLL) is an aggressive and fatal malignancy of CD4+ T-lymphocytes associated with HTLV-1 infection, and an effective treatment is not yet available. The exact molecular mechanism underlying ATLL has not been fully elucidated. Although the activation of cell proliferation and inhibition of tumor suppressors are considered key contributors to the leukemogenesis process, the accumulation of DNA damage and genomic instability are believed to be the driving force for tumorigenesis and are known to be a hallmark of cancer cells. How genomic instability accumulates in cancer remains an elusive question. One of the most serious forms of genomic instability is DNA Double Strand Breaks (DDSB) because they pose problems for transcription, replication and chromosome segregation. We have recently shown that the HTLV-1 oncoprotein Tax induces DDSB. In addition, Tax has been found to constitutively activate the key T-cell inflammatory pathway, NF-kB, and this activation is critical for the leukemogenic process associated with HTLV-1 infection. In the present study, we investigated whether any of the NF-kB target genes is critical in inducing DDSB. Of note, we found that the inducible nitric oxide synthase (iNOS), the enzyme that catalyzes the production of nitric oxide (NO) in T-cells, is a target of the NF-kB pathway and is highly expressed in HTLV-1 and Tax expressing cells. Nitric oxide is an important cellular signaling molecule involved in many physiological and pathological processes and is a part of the network of reactive species that inflict DNA damage as a defense mechanism after infection. Interestingly, our results show a correlation between the number of DDSB and the production of NO in tumors isolated from Tax transgenic mice. We also observed a dramatic reduction of DDSB when NO production was inhibited, indicating that Tax induces DNA damage through the activation of NO. Determination of the impact of NO on tumors in an ATLL mouse model will open a new area in the development of alternative strategies for the treatment/prevention of ATLL, and the conclusions will be directly relevant to a better understanding of many types of cancer.
Citation Format: Hicham Baydoun, Lee Ratner. HTLV-1 Tax inflicts severe DNA damage through the activation of nitric oxide production: A credible pathway for transformation of HTLV-1 infected 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 LB-127. doi:10.1158/1538-7445.AM2013-LB-127
Abstract LB-128: High throughput screening kinase activators of Atg4B for cancer therapy.
Authors: Shu Chih-Wen , Liu Pei-Feng , Reed John C. 
Published: August 2014

Abstract
Autophagy is an evolutionarily conserved process whereby cells catabolize damaged proteins and organelles for purposes of generating substrates for sustaining ATP production during times of nutrient deprivation. This self-eating process is associated with many diseases, particular in cancers. The theory remains controversial due to limitation of the assays about autophagy, which requires specific assays and further studies to reevaluate the role of autophagy on cancer cells. Autophagins/Atg4 are a class of cytosolic cysteine proteases and play dual roles in autophagy machinery, suggesting tightly control of Atg4 is critical for regulation of autophagy. There are four human genes encoding Atg4 (Atg4A, Atg4B, Atg4C, Atg4D). Among them, Atg4B appears functional dominance in regulation of autophagy. Knocking down Atg4B or overexpression of catalytic mutant of Atg4B inhibited cell growth in various cancer cells. Moreover, Atg4B reveals three phosphorylation sites at Ser 316, 383, 392 in cells through large-scale phosphoproteomics approach. Inhibiting phosphorylation of Atg4B diminished proteolysis activity both in vitro and in cells, suggesting kinases may serve as activators for Atg4B. Further, we employed mammalian cell-based Atg4B assay to screen potential kinases activators of Atg4B with kinome siRNA library, which consists 704 kinase related genes. Twelve hits were reproducible and reconfirmed with GFP-LC3 stably expressed cells as a secondary assay. Four kinase hits were interacted with Atg4B and showed same effect on GFP-LC3 cleavage. Knocking down kinase hits diminished Atg4B proteolysis activity and cell growth in cancer cells, demonstrating novel function of the kinase hits on Atg4B-mediated autophagy and cancer growth. Our finding may provide new kinases as biomarkers or drug targets for cancer therapy.
Citation Format: Chih-Wen Shu, Pei-Feng Liu, John C. Reed. High throughput screening kinase activators of Atg4B for cancer therapy. [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 LB-128. doi:10.1158/1538-7445.AM2013-LB-128
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract LB-130: The metabolic function of RB tumor suppressor gene.
Authors: Kohno Susumu , Kitajima Shunsuke , Sasaki Nobunari , Muranaka Hayato , Takahashi Chiaki 
Published: August 2014

Abstract
The RB tumor suppressor gene has been implicated primarily in the control of cell cycle and terminal differentiation. However recent findings indicate that pRB may possess much more roles than previously thought (Viatour & Sage, Dis. Model Mech., 4: 581, 2011; Takahashi et al., Cancer Sci., 103: 1182, 2012). We have been exploring unique roles of pRB using mice with various genetic backgrounds (Takahashi et al., Nat. Genet., 38: 118, 2006). A seminal observation in nematode prompted us to address how pRB controls Ras activation status. We previously reported that pRB regulates mevalonate (MVA) pathway through SREBPs thus affects isoprenylation of Ras proteins (Shamma et al., Cancer Cell 15:255, 2009). We are currently extending this observation to the investigation of pRB roles in controlling cellular metabolism. We identified a number of metabolic pathways that are affected by the status of RB in various cellular contexts and genetic backgrounds. Furthermore, a recent report from another group pointed out that the product of mutated p53 tumor suppressor gene also targets SREBP although in a different fashion (Freed-Pastor et al., Cell 148: 244, 2012). We therefore hypothesized that these two tumor suppressors are redundant in the control of lipid synthesis. As expected, depending on the context, mouse cells deficient of both Rb and p53 genes showed evidence of metabolic reprogramming and moreover features of cancer stem cells. In addition, mice deficient of both genes generated tumors with unique undifferentiated phenotypes associated with many kinds of cancer stem cell-like activities. We further analyzed such cells or tumor cells by transcriptomics, metabolomics, flux analyzer and high-throughput drug screening methods: these unveiled previously unexpected functions of pRB in controlling cell metabolism and stemness (Kohno et al., in preparation for submission).
Citation Format: Susumu Kohno, Shunsuke Kitajima, Nobunari Sasaki, Hayato Muranaka, Chiaki Takahashi. The metabolic function of RB tumor suppressor gene. [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 LB-130. doi:10.1158/1538-7445.AM2013-LB-130
Abstract LB-14: High-risk cervical human papillomavirus infections among human immunodeficiency virus-positive women in the Bahamas.
Authors: Blackman Elizabeth , Dames Dionne N. , Butler Raleigh , Taioli Emanuela , Eckstein Stacy , Devarajan Karthik , Griffith-Bowe Andrea , Gomez Perry , Ragin Camille 
Published: August 2014

Abstract
Background: It has been demonstrated in immunocompromised females that HR HPV genotypes other than 16 and 18 have been detected in a significant proportion of these individuals. We aim to evaluate the frequency of HR HPV genotypes in a population of HIV-positive Caribbean women, detect characteristics associated with HR HPV infections other than HPV16 and 18, and investigate the clustering of HPV genotypes in this population.
Methods: One hundred and seventy-six non-pregnant, HIV-positive females ≥18 years were recruited. Each participant received a vaginal examination and completed a questionnaire.
Results: Mean age was 38.7 years for women positive for HR HPV and 44.4 years for women negative for HR HPV (P value = 0.0018). The majority of the HR HPV-positive women were on HAART for 2-4 years. Non-negative matrix factorization identified HPV 16, 18, 52 and 58 as the most influential HPV high-risk types. Among the women who were HIV+ for more than 2 years, secondary CART analysis revealed those aged ≤29 had statistically significant different cervical abnormality profile compared to women &gt;29 years; specifically, younger women were more likely to have dysplasia, while older women had normal cervical cytology. Also, the mean number of years on HAART for ≤29 years old was only 1 year (std dev. ±1.3) while those &gt;29 years old the mean was 3.6 years (std. dev. ± 2.5) (p = 0.009).
Conclusions: HR HPV in the immunocompromised female consists of more than just HPV 16 and 18, but also types HPV 52 and 58, which are likely to influence the course of HPV infections and the development of cervical cytological abnormalities. Targeted interventions to boost treatment compliance among HIV- positive women are needed to reduce the risk of cervical abnormalities.
Citation Format: Elizabeth Blackman, Dionne N. Dames, Raleigh Butler, Emanuela Taioli, Stacy Eckstein, Karthik Devarajan, Andrea Griffith-Bowe, Perry Gomez, Camille Ragin. High-risk cervical human papillomavirus infections among human immunodeficiency virus-positive women in the Bahamas. [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 LB-14. doi:10.1158/1538-7445.AM2013-LB-14
Abstract LB-149: Sustained activity of the mTOR pathway is required for DNA damage-induced up-regulation of RRM2 in cancer cells.
Authors: Shen Changxian , Houghton Peter J. 
Published: August 2014

Abstract
Balanced deoxyribonucleotides (dNTPs) are essential for the accurate and efficient replication and repair DNA synthesis. Increased or imbalanced dNTP pool leads to a mutator phenotype, while decreased dNTP level impairs DNA replication and repair, and hence cell survival. Ribonucleotide reductase (RNR) is the rate-limiting enzyme for the production of dNTPs from ribonucleotides and is under tight control during cell cycle and in response to stress. Increase of RNR is required for yeast cells to survive DNA damage and replication stress. However, the regulation and function of RNR in response to DNA damage remains unclear and controversial in mammalian cells. We report here that the mTOR pathway controls both RRM1 and RRM2 but not p53R2. mTOR signaling is required for mitomycin C (MMC) induced up-regulation of RRM2 in rhabdomyosarcoma Rh30 cells. Pharmacological inhibition of mTOR kinase with AZD8055 or mTORC1 inhibitor rapamycin resulted in the decrease of both RRM1 and RRM2, but not p53R2. 4E-BP1 and 4E-BP2 double knockout mouse embryonic fibroblast cells (4E-BP1/2-/- MEF) showed increased basal expression of RRM1 and RRM2, indicating that mTORC1 controls RRM1 and RRM2 via cap-dependent protein translation. In addition, pharmacological inhibition of either mTORC2-Akt signaling or CDK4/6 led to decrease of the mRNAs of RRM1 and RRM2, accompanied with the suppression of pRb-S780 signaling, suggesting that mTORC2-Akt signaling controls the gene transcription of RRM1 and RRM2 via regulating G1 cyclin-dependent kinases (CDK4/6). Both rapamycin and AZD8055 impaired the induction of endogenous RRM2 by MMC, but not ectopically expressed RRM2, which is not controlled by mTOR signaling. Our data demonstrate that mTOR controls both the protein translation and gene transcription of RRM1 and RRM2. DNA damage induced up-regulation of RRM2 depends on sustained mTOR signaling, suggesting that control of RNR by mTOR signaling may be one of the mechanisms by which cell growth-promoting signaling pathways enhance the survival and genome instability of cancer cells under constant DNA replication and damage induced stress. Supported by UPHS award CA77776.
Citation Format: Changxian Shen, Peter J. Houghton. Sustained activity of the mTOR pathway is required for DNA damage-induced up-regulation of RRM2 in 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 LB-149. doi:10.1158/1538-7445.AM2013-LB-149