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2. Genome-Wide Methylation Profiling of Peripheral T–Cell Lymphomas Identifies TRIP13 as a Critical Driver of Tumor Proliferation and Survival.

Author

Nowialis, Pawel, Tobon, Julian, Lopusna, Katarina, Opavska, Jana, Badar, Arshee, Chen, Duo, Abdelghany, Reem, Pozas, Gene, Fingeret, Jacob, Noel, Emma, Riva, Alberto, Fujiwara, Hiroshi, Ishov, Alexander, and Opavsky, Rene

Subjects
GENETIC regulation, THYROID hormone receptors, DNA methyltransferases, DNA methylation, GENE expression
Abstract

Cytosine methylation contributes to the regulation of gene expression and normal hematopoiesis in mammals. It is catalyzed by the family of DNA methyltransferases that include DNMT1, DNMT3A, and DNMT3B. Peripheral T–cell lymphomas (PTCLs) represent aggressive mature T–cell malignancies exhibiting a broad spectrum of clinical features with poor prognosis and inadequately understood molecular pathobiology. To better understand the molecular landscape and identify candidate genes involved in disease maintenance, we profiled DNA methylation and gene expression of PTCLs. We found that the methylation patterns in PTCLs are deregulated and heterogeneous but share 767 hypo- and 567 hypermethylated differentially methylated regions (DMRs) along with 231 genes up- and 91 genes downregulated in all samples, suggesting a potential association with tumor development. We further identified 39 hypomethylated promoters associated with increased gene expression in the majority of PTCLs. This putative oncogenic signature included the TRIP13 (thyroid hormone receptor interactor 13) gene whose genetic and pharmacologic inactivation inhibited the proliferation of T–cell lines by inducing G2-M arrest and apoptosis. Our data thus show that human PTCLs have a significant number of recurrent methylation alterations that may affect the expression of genes critical for proliferation whose targeting might be beneficial in anti-lymphoma treatments. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Genome-wide methylation profiling of Peripheral T-cell lymphomas identifies TRIP13 as a critical driver of tumor proliferation and survival

Author

Nowialis, Pawel, primary, Tobon, Julian, additional, Lopusna, Katarina, additional, Opavska, Jana, additional, Badar, Arshee, additional, Chen, Duo, additional, Abdelghany, Reem, additional, Pozas, Gene, additional, Fingeret, Jacob, additional, Noel, Emma, additional, Riva, Alberto, additional, Fujiwara, Hiroshi, additional, and Opavsky, Rene, additional

Published
2024
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4. Dormant Cancer Cells Contribute to Residual Disease in a Model of Reversible Pancreatic Cancer

Author

Lin, Wan-chi, Rajbhandari, Nirakar, Liu, Chengbao, Sakamoto, Kazuhito, Zhang, Qian, Triplett, Aleata A, Batra, Surinder K, Opavsky, Rene, Felsher, Dean W, DiMaio, Dominick J, Hollingsworth, Michael A, Morris, John P, Hebrok, Matthias, Witkiewicz, Agnieszka K, Brody, Jonathan R, Rui, Hallgeir, and Wagner, Kay-Uwe

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Genetics, Pancreatic Cancer, Stem Cell Research, Rare Diseases, Cancer, Stem Cell Research - Nonembryonic - Non-Human, Biotechnology, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Animals, Cell Transformation, Neoplastic, Disease Models, Animal, Flow Cytometry, Genes, myc, Genes, p16, Mice, Neoplasm Recurrence, Local, Pancreatic Neoplasms, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

The initiation and progression of pancreatic ductal adenocarcinoma (PDAC) is governed by a series of genetic and epigenetic changes, but it is still unknown whether these alterations are required for the maintenance of primary and metastatic PDAC. We show here that the c-Myc oncogene is upregulated throughout the entire process of neoplastic progression in human PDAC and in genetically engineered mice that express mutant Kras. To experimentally address whether c-Myc is essential for the growth and survival of cancer cells, we developed a novel mouse model that allows a temporally and spatially controlled expression of this oncogene in pancreatic progenitors and derived lineages of the exocrine pancreas. Unlike previous reports, upregulation of c-Myc was sufficient to induce the formation of adenocarcinomas after a short latency without additional genetic manipulation of cell survival pathways. Deficiency in Cdkn2a increased the rate of metastasis but had no effect on tumor latency or c-Myc-mediated cancer maintenance. Despite a macroscopically complete regression of primary, metastatic, and transplantable tumors following the ablation of c-Myc, some cancer cells remained dormant. A significant number of these residual neoplastic cells expressed cancer stem cell markers, and re-expression of exogenous c-Myc in these cells led to rapid cancer recurrence. Collectively, the results of this study suggest that c-Myc plays a significant role in the progression and maintenance of PDAC, but besides targeting this oncogene or its downstream effectors, additional therapeutic strategies are necessary to eradicate residual cancer cells to prevent disease recurrence.

Published
2013

5. Supplementary Data from DNMT3A Harboring Leukemia-Associated Mutations Directs Sensitivity to DNA Damage at Replication Forks

Author

Venugopal, Kartika, primary, Feng, Yang, primary, Nowialis, Pawel, primary, Xu, Huanzhou, primary, Shabashvili, Daniil E., primary, Berntsen, Cassandra M., primary, Kaur, Prabhjot, primary, Krajcik, Kathryn I., primary, Taragjini, Christina, primary, Zaroogian, Zachary, primary, Casellas Román, Heidi L., primary, Posada, Luisa M., primary, Gunaratne, Chamara, primary, Li, Jianping, primary, Dupéré-Richer, Daphné, primary, Bennett, Richard L., primary, Pondugula, Santhi, primary, Riva, Alberto, primary, Cogle, Christopher R., primary, Opavsky, Rene, primary, Law, Brian K., primary, Bhaduri-McIntosh, Sumita, primary, Kubicek, Stefan, primary, Staber, Philipp B., primary, Licht, Jonathan D., primary, Bird, Jonathan E., primary, and Guryanova, Olga A., primary

Published
2023
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6. Data from Dormant Cancer Cells Contribute to Residual Disease in a Model of Reversible Pancreatic Cancer

Author

Lin, Wan-chi, primary, Rajbhandari, Nirakar, primary, Liu, Chengbao, primary, Sakamoto, Kazuhito, primary, Zhang, Qian, primary, Triplett, Aleata A., primary, Batra, Surinder K., primary, Opavsky, Rene, primary, Felsher, Dean W., primary, DiMaio, Dominick J., primary, Hollingsworth, Michael A., primary, Morris, John P., primary, Hebrok, Matthias, primary, Witkiewicz, Agnieszka K., primary, Brody, Jonathan R., primary, Rui, Hallgeir, primary, and Wagner, Kay-Uwe, primary

Published
2023
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7. Supplementary Methods from Dormant Cancer Cells Contribute to Residual Disease in a Model of Reversible Pancreatic Cancer

Author

Lin, Wan-chi, primary, Rajbhandari, Nirakar, primary, Liu, Chengbao, primary, Sakamoto, Kazuhito, primary, Zhang, Qian, primary, Triplett, Aleata A., primary, Batra, Surinder K., primary, Opavsky, Rene, primary, Felsher, Dean W., primary, DiMaio, Dominick J., primary, Hollingsworth, Michael A., primary, Morris, John P., primary, Hebrok, Matthias, primary, Witkiewicz, Agnieszka K., primary, Brody, Jonathan R., primary, Rui, Hallgeir, primary, and Wagner, Kay-Uwe, primary

Published
2023
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8. Supplementary Table 1 from Dormant Cancer Cells Contribute to Residual Disease in a Model of Reversible Pancreatic Cancer

Author

Lin, Wan-chi, primary, Rajbhandari, Nirakar, primary, Liu, Chengbao, primary, Sakamoto, Kazuhito, primary, Zhang, Qian, primary, Triplett, Aleata A., primary, Batra, Surinder K., primary, Opavsky, Rene, primary, Felsher, Dean W., primary, DiMaio, Dominick J., primary, Hollingsworth, Michael A., primary, Morris, John P., primary, Hebrok, Matthias, primary, Witkiewicz, Agnieszka K., primary, Brody, Jonathan R., primary, Rui, Hallgeir, primary, and Wagner, Kay-Uwe, primary

Published
2023
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9. Supplementary Figure Legend from Dormant Cancer Cells Contribute to Residual Disease in a Model of Reversible Pancreatic Cancer

Author

Lin, Wan-chi, primary, Rajbhandari, Nirakar, primary, Liu, Chengbao, primary, Sakamoto, Kazuhito, primary, Zhang, Qian, primary, Triplett, Aleata A., primary, Batra, Surinder K., primary, Opavsky, Rene, primary, Felsher, Dean W., primary, DiMaio, Dominick J., primary, Hollingsworth, Michael A., primary, Morris, John P., primary, Hebrok, Matthias, primary, Witkiewicz, Agnieszka K., primary, Brody, Jonathan R., primary, Rui, Hallgeir, primary, and Wagner, Kay-Uwe, primary

Published
2023
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10. Supplementary Figures 1 - 8 from Dormant Cancer Cells Contribute to Residual Disease in a Model of Reversible Pancreatic Cancer

Author

Lin, Wan-chi, primary, Rajbhandari, Nirakar, primary, Liu, Chengbao, primary, Sakamoto, Kazuhito, primary, Zhang, Qian, primary, Triplett, Aleata A., primary, Batra, Surinder K., primary, Opavsky, Rene, primary, Felsher, Dean W., primary, DiMaio, Dominick J., primary, Hollingsworth, Michael A., primary, Morris, John P., primary, Hebrok, Matthias, primary, Witkiewicz, Agnieszka K., primary, Brody, Jonathan R., primary, Rui, Hallgeir, primary, and Wagner, Kay-Uwe, primary

Published
2023
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13. DNMT3A Harboring Leukemia-Associated Mutations Directs Sensitivity to DNA Damage at Replication Forks

Author

Venugopal, Kartika, primary, Feng, Yang, additional, Nowialis, Pawel, additional, Xu, Huanzhou, additional, Shabashvili, Daniil E., additional, Berntsen, Cassandra M., additional, Kaur, Prabhjot, additional, Krajcik, Kathryn I., additional, Taragjini, Christina, additional, Zaroogian, Zachary, additional, Casellas Román, Heidi L., additional, Posada, Luisa M., additional, Gunaratne, Chamara, additional, Li, Jianping, additional, Dupéré-Richer, Daphné, additional, Bennett, Richard L., additional, Pondugula, Santhi, additional, Riva, Alberto, additional, Cogle, Christopher R., additional, Opavsky, Rene, additional, Law, Brian K., additional, Bhaduri-McIntosh, Sumita, additional, Kubicek, Stefan, additional, Staber, Philipp B., additional, Licht, Jonathan D., additional, Bird, Jonathan E., additional, and Guryanova, Olga A., additional

Published
2021
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15. Loss of Dnmt3b function upregulates the tumor modifier Ment and accelerates mouse lymphomagenesis

Author

Hlady, Ryan A., Novakova, Slavomira, Opavska, Jana, Klinkebiel, David, Peters, Staci L., Bies, Juraj, Hannah, Jay, Iqbal, Javeed, Anderson, Kristi M., Siebler, Hollie M., Smith, Lynette M., Greiner, Timothy C., Bastola, Dhundy, Joshi, Shantaram, Lockridge, Oksana, Simpson, Melanie A., Felsher, Dean W., Wagner, Kay-Uwe, Chan, Wing C., Christman, Judith K., and Opavsky, Rene

Subjects
T cells -- Physiological aspects -- Research, Methylation -- Research, Lymphomas -- Diagnosis -- Genetic aspects -- Research -- Care and treatment, Methyltransferases -- Physiological aspects -- Research, Health care industry
Abstract

DNA methyltransferase 3B (Dnmt3b) belongs to a family of enzymes responsible for methylation of cytosine residues in mammals. DNA methylation contributes to the epigenetic control of gene transcription and is deregulated in virtually all human tumors. To better understand the generation of cancer-specific methylation patterns, we genetically inactivated Dnmt3b in a mouse model of MYC-induced lymphomagenesis. Ablation of Dnmt3b function using a conditional knockout in T cells accelerated lymphomagenesis by increasing cellular proliferation, which suggests that Dnmt3b functions as a tumor suppressor. Global methylation profiling revealed numerous gene promoters as potential targets of Dnmt3b activity, the majority of which were demethylated in Dnmt[3b.sup.-/-] lymphomas, but not in Dnmt[3b.sup.-/-] pretumor thymocytes, implicating Dnmt3b in maintenance of cytosine methylation in cancer. Functional analysis identified the gene Gm128 (which we termed herein methylated in normal thymocytes [Ment]) as a target of Dnmt3b activity. We found that Ment was gradually demethylated and overexpressed during tumor progression in Dnmt[3b.sup.-/-] lymphomas. Similarly, MENT was overexpressed in 67% of human lymphomas, and its transcription inversely correlated with methylation and levels of DNMT3B. Importantly, knockdown of Ment inhibited growth of mouse and human cells, whereas overexpression of Ment provided Dnmt[3b.sup.+/+] cells with a proliferative advantage. Our findings identify Ment as an enhancer of lymphomagenesis that contributes to the tumor suppressor function of Dnmt3b and suggest it could be a potential target for anticancer therapies., Introduction Cytosine methylation represents a heritable epigenetic modification affecting gene transcription and the integrity of the genome. The DNA methyltransferases (DNMTs) DNMT1, DNMT3A, and DNMT3B are the enzymes primarily responsible [...]

Published
2012
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18. Mouse development with a single E2F activator

Author

Tsai, Shin-Yin, Opavsky, Rene, Sharma, Nidhi, Wu, Lizhao, Naidu, Shan, Nolan, Eric, Feria-Arias, Enrique, Timmers, Cynthia, Opavska, Jana, De Bruin, Alain, Chong, Jean-Leon, Trikha, Prashant, Fernandez, Soledad A., Stromberg, Paul, Rosol, Thomas J., and Leone, Gustavo

Subjects
DNA binding proteins -- Physiological aspects -- Properties -- Genetic aspects -- Growth, Mice -- Growth -- Genetic aspects -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation, Company growth, Physiological aspects, Genetic aspects, Growth, Properties
Abstract

The E2F family is conserved from Caenorhabditis elegans to mammals, with some family members having transcription activation functions and others having repressor functions (1-2). Whereas C. elegann (3) and Drosophila [...]

Published
2008

23. Catalytically inactive Dnmt3b rescues mouse embryonic development by accessory and repressive functions

Author

Nowialis, Pawel, primary, Lopusna, Katarina, additional, Opavska, Jana, additional, Haney, Staci L., additional, Abraham, Ajay, additional, Sheng, Peike, additional, Riva, Alberto, additional, Natarajan, Amarnath, additional, Guryanova, Olga, additional, Simpson, Melanie, additional, Hlady, Ryan, additional, Xie, Mingyi, additional, and Opavsky, Rene, additional

Published
2019
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25. C17ORF58Is Upregulated in Peripheral T-Cell Lymphomas and Encodes a Protein Critical for Survival of PTCL Cells

Author

Tobon, Julian, Nowialis, Pawel, Lopusna, Katarina, Chen, Duo, Badar, Arshee, Abdelghany, Reem, Noel, Emma, Fingeret, Jacob, Pozas, Gene, Opavska, Jana, Fujiwara, Hiroshi, and Opavsky, Rene

Abstract

Peripheral T-cell lymphomas (PTCL) constitute a group of heterogeneous T- and NK-cell malignancies, accounting for about 15% of Non-Hodgkin lymphomas (NHL). Most PTCL subtypes exhibit an aggressive disease presentation, carrying a worse prognosis than B-cell lymphomas. PTCL - Not Otherwise Specified (PTCL-NOS), the largest subgroup, is categorized by exclusion, with a diagnosis given if the patient does not meet the diagnostic criteria of other PTCL subtypes. PTCL-NOS is a heterogeneous group with diverse cells of origin, varied cytogenic, molecular, and morphological phenotypes, and antigen variability. Despite the increase in specific T-cell lymphoma treatment options, such as belinostat, romidepsin, pralatrexate, and brentuximab vedotin, alongside conventional non-targeted chemotherapy like CHOP and R-CHOP, the overall 5 year survival remains only at 20-30%. A deeper understanding of the pathways and genes critical for PTCL-NOS survival is urgently needed.

Published
2023
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30. Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a

Author

Haney, Staci L., primary, Upchurch, G. Michael, additional, Opavska, Jana, additional, Klinkebiel, David, additional, Hlady, Ryan A., additional, Suresh, Abhinav, additional, Pirruccello, Samuel J., additional, Shukla, Vipul, additional, Lu, Runqing, additional, Costinean, Stefan, additional, Rizzino, Angie, additional, Karpf, Adam R., additional, Joshi, Shantaram, additional, Swanson, Patrick, additional, and Opavsky, Rene, additional

Published
2016
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32. Immature truncated O-glycophenotype of cancer directly induces oncogenic features

Author

Radhakrishnan, Prakash, Dabelsteen, Sally, Madsen, Frey Brus, Francavilla, Chiara, Kopp, Katharina L, Steentoft, Catharina, Vakhrushev, Sergey Y, Olsen, Jesper V, Hansen, Lars, Bennett, Eric P, Woetmann, Anders, Yin, Guangliang, Chen, Longyun, Song, Haiyan, Bak, Mads, Hlady, Ryan A, Peters, Staci L, Opavsky, Rene, Thode, Christenze, Qvortrup, Klaus, Schjoldager, Katrine Ter-Borch Gram, Clausen, Henrik, Hollingsworth, Michael A, Wandall, Hans H, Radhakrishnan, Prakash, Dabelsteen, Sally, Madsen, Frey Brus, Francavilla, Chiara, Kopp, Katharina L, Steentoft, Catharina, Vakhrushev, Sergey Y, Olsen, Jesper V, Hansen, Lars, Bennett, Eric P, Woetmann, Anders, Yin, Guangliang, Chen, Longyun, Song, Haiyan, Bak, Mads, Hlady, Ryan A, Peters, Staci L, Opavsky, Rene, Thode, Christenze, Qvortrup, Klaus, Schjoldager, Katrine Ter-Borch Gram, Clausen, Henrik, Hollingsworth, Michael A, and Wandall, Hans H

Abstract

Aberrant expression of immature truncated O-glycans is a characteristic feature observed on virtually all epithelial cancer cells, and a very high frequency is observed in early epithelial premalignant lesions that precede the development of adenocarcinomas. Expression of the truncated O-glycan structures Tn and sialyl-Tn is strongly associated with poor prognosis and overall low survival. The genetic and biosynthetic mechanisms leading to accumulation of truncated O-glycans are not fully understood and include mutation or dysregulation of glycosyltransferases involved in elongation of O-glycans, as well as relocation of glycosyltransferases controlling initiation of O-glycosylation from Golgi to endoplasmic reticulum. Truncated O-glycans have been proposed to play functional roles for cancer-cell invasiveness, but our understanding of the biological functions of aberrant glycosylation in cancer is still highly limited. Here, we used exome sequencing of most glycosyltransferases in a large series of primary and metastatic pancreatic cancers to rule out somatic mutations as a cause of expression of truncated O-glycans. Instead, we found hypermethylation of core 1 β3-Gal-T-specific molecular chaperone, a key chaperone for O-glycan elongation, as the most prevalent cause. We next used gene editing to produce isogenic cell systems with and without homogenous truncated O-glycans that enabled, to our knowledge, the first polyomic and side-by-side evaluation of the cancer O-glycophenotype in an organotypic tissue model and in xenografts. The results strongly suggest that truncation of O-glycans directly induces oncogenic features of cell growth and invasion. The study provides support for targeting cancer-specific truncated O-glycans with immunotherapeutic measures.

Published
2014

34. Immature truncated O-glycophenotype of cancer directly induces oncogenic features

Author

Radhakrishnan, Prakash, primary, Dabelsteen, Sally, additional, Madsen, Frey Brus, additional, Francavilla, Chiara, additional, Kopp, Katharina L., additional, Steentoft, Catharina, additional, Vakhrushev, Sergey Y., additional, Olsen, Jesper V., additional, Hansen, Lars, additional, Bennett, Eric P., additional, Woetmann, Anders, additional, Yin, Guangliang, additional, Chen, Longyun, additional, Song, Haiyan, additional, Bak, Mads, additional, Hlady, Ryan A., additional, Peters, Staci L., additional, Opavsky, Rene, additional, Thode, Christenze, additional, Qvortrup, Klaus, additional, Schjoldager, Katrine T.-B. G., additional, Clausen, Henrik, additional, Hollingsworth, Michael A., additional, and Wandall, Hans H., additional

Published
2014
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39. E2f1–3 Are Critical for Myeloid Development

Author

Trikha, Prashant, primary, Sharma, Nidhi, additional, Opavsky, Rene, additional, Reyes, Andres, additional, Pena, Clarissa, additional, Ostrowski, Michael C., additional, Roussel, Martine F., additional, and Leone, Gustavo, additional

Published
2011
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42. CpG Island Methylation in a Mouse Model of Lymphoma Is Driven by the Genetic Configuration of Tumor Cells

Author

Opavsky, Rene, primary, Wang, Shu-Huei, additional, Trikha, Prashant, additional, Raval, Aparna, additional, Huang, Yuan, additional, Wu, Yue-Zhong, additional, Rodriguez, Benjamin, additional, Keller, Benjamin, additional, Liyanarachchi, Sandya, additional, Wei, Guo, additional, Davuluri, Ramana V, additional, Weinstein, Michael, additional, Felsher, Dean, additional, Ostrowski, Michael, additional, Leone, Gustavo, additional, and Plass, Christoph, additional

Published
2007
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46. CpG Island Methylation in a Mouse Model of Lymphoma Is Driven by the Genetic Configuration of Tumor Cells

Author

Opavsky, Rene, primary, Wang, Shu-Huei, additional, Trikha, Prashant, additional, Raval, Aparna, additional, Huang, Yuan, additional, Wu, Yue-Zhong, additional, Rodriguez, Benjamin, additional, Keller, Benjamin, additional, Liyanarachchi, Sandya, additional, Wei, Guo, additional, Davuluri, Ramana V, additional, Weinstein, Michael, additional, Felsher, Dean W., additional, Ostrowski, Michael, additional, Leone, Gustavo Walter, additional, and Plass, Christoph, additional

Published
2005
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48. Molecular Characterization of the MouseTem1/endosialin Gene Regulated by Cell Density in Vitro and Expressed in Normal Tissues in Vivo

Author

Opavsky, Rene, primary, Haviernik, Peter, additional, Jurkovicova, Dana, additional, Garin, Matthew T., additional, Copeland, Neal G., additional, Gilbert, Debbra J., additional, Jenkins, Nancy A., additional, Bies, Juraj, additional, Garfield, Susan, additional, Pastorekova, Silvia, additional, Oue, Atsushi, additional, and Wolff, Linda, additional

Published
2001
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49. E2f3a and E2f3b Contribute to the Control of Cell Proliferation and Mouse Development.

Author

Jean-Leon Chong, Shih-Yin Tsai, Sharma, Nidhi, Opavsky, Rene, Price, Richard, Lizhao Wu, Fernandez, Soledad A., and Leone, Gustavo

Subjects
GENES, CELL proliferation, CELL cycle, CHROMATIN, GENE expression, EXPERIMENTS, FIBROBLASTS
Abstract

The E2f3 locus encodes two Rb-binding gene products, E2F3a and E2F3b, which are differentially regulated during the cell cycle and are thought to be critical for cell cycle progression. We targeted the individual inactivation of E2f3a or E2f3b in mice and examined their contributions to cell proliferation and development. Chromatin immunoprecipitation and gene expression experiments using mouse embryo fibroblasts deficient in each isoform showed that E2F3a and E2F3b contribute to G1/S-specific gene expression and cell proliferation. Expression of E2f3a or E2f3b was sufficient to support E2F target gene expression and cell proliferation in the absence of other E2F activators, E2f1 and E2f2, suggesting that these isoforms have redundant functions. Consistent with this notion, E2f3a-/- and E2f3b-/- embryos developed normally, whereas embryos lacking both isoforms (E2f3-/-) died in utero. We also find that E2f3a and E2f3b have redundant and nonredundant roles in the context of Rb mutation. Analysis of double-knockout embryos suggests that the ectopic proliferation and apoptosis in Rb-/- embryos is mainly mediated by E2f3a in the placenta and nervous system and by both E2f3a and E2f3b in lens fiber cells. Together, we conclude that the contributions of E2F3a and E2F3b in cell proliferation and development are context dependent. [ABSTRACT FROM AUTHOR]

Published
2009
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50. Mouse development with a single E2F activator.

Author

Shih-Yin Tsai, Opavsky, Rene, Sharma, Nidhi, Lizhao Wu, Naidu, Shan, Nolan, Eric, Feria-Arias, Enrique, Timmers, Cynthia, Opavska, Jana, de Bruin, Alain, Chong, Jean-Leon, Trikha, Prashant, Fernandez, Soledad A., Stromberg, Paul, Rosol, Thomas J., and Leone, Gustavo

Subjects
*CAENORHABDITIS elegans, *MAMMALS, *GENETIC repressors, *PROTEINS, *PHENOTYPES, *MICE, *EMBRYOLOGY, *DROSOPHILA melanogaster, *GENETICS
Abstract

The E2F family is conserved from Caenorhabditis elegans to mammals, with some family members having transcription activation functions and others having repressor functions. Whereas C. elegans and Drosophila melanogaster have a single E2F activator protein and repressor protein, mammals have at least three activator and five repressor proteins. Why such genetic complexity evolved in mammals is not known. To begin to evaluate this genetic complexity, we targeted the inactivation of the entire subset of activators, E2f1, E2f2, E2f3a and E2f3b, singly or in combination in mice. We demonstrate that E2f3a is sufficient to support mouse embryonic and postnatal development. Remarkably, expression of E2f3b or E2f1 from the E2f3a locus (E2f3a3bki or E2f3a1ki, respectively) suppressed all the postnatal phenotypes associated with the inactivation of E2f3a. We conclude that there is significant functional redundancy among activators and that the specific requirement for E2f3a during postnatal development is dictated by regulatory sequences governing its selective spatiotemporal expression and not by its intrinsic protein functions. These findings provide a molecular basis for the observed specificity among E2F activators during development. [ABSTRACT FROM AUTHOR]

Published
2008
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