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  • 1
    Publication Date: 2012-05-26
    Description: Tumors exhibit numerous recurrent hemizygous focal deletions that contain no known tumor suppressors and are poorly understood. To investigate whether these regions contribute to tumorigenesis, we searched genetically for genes with cancer-relevant properties within these hemizygous deletions. We identified STOP and GO genes, which negatively and positively regulate proliferation, respectively. STOP genes include many known tumor suppressors, whereas GO genes are enriched for essential genes. Analysis of their chromosomal distribution revealed that recurring deletions preferentially overrepresent STOP genes and underrepresent GO genes. We propose a hypothesis called the cancer gene island model, whereby gene islands encompassing high densities of STOP genes and low densities of GO genes are hemizygously deleted to maximize proliferative fitness through cumulative haploinsufficiencies. Because hundreds to thousands of genes are hemizygously deleted per tumor, this mechanism may help to drive tumorigenesis across many cancer types.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027969/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027969/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Solimini, Nicole L -- Xu, Qikai -- Mermel, Craig H -- Liang, Anthony C -- Schlabach, Michael R -- Luo, Ji -- Burrows, Anna E -- Anselmo, Anthony N -- Bredemeyer, Andrea L -- Li, Mamie Z -- Beroukhim, Rameen -- Meyerson, Matthew -- Elledge, Stephen J -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM07753/GM/NIGMS NIH HHS/ -- U54CA143798/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 Jul 6;337(6090):104-9. doi: 10.1126/science.1219580. Epub 2012 May 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard University Medical School, and Division of Genetics, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22628553" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Cell Line, Tumor ; *Cell Proliferation ; *Cell Transformation, Neoplastic ; Chromosome Mapping ; Genes, Essential ; *Genes, Neoplasm ; Genes, Recessive ; Genes, Tumor Suppressor ; *Haploinsufficiency ; Hemizygote ; Humans ; Models, Genetic ; Neoplasms/*genetics/*pathology ; Oncogenes ; *Sequence Deletion
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-12-14
    Description: Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we used a genome-wide RNA interference screen to search for Myc-synthetic lethal genes and uncovered a role for the SUMO-activating enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Inactivation of SAE2 leads to mitotic catastrophe and cell death upon Myc hyperactivation. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent Myc switchers (SMS genes) is required for mitotic spindle function and to support the Myc oncogenic program. SAE2 is required for growth of Myc-dependent tumors in mice, and gene expression analyses of Myc-high human breast cancers suggest that low SAE1 and SAE2 abundance in the tumors correlates with longer metastasis-free survival of the patients. Thus, inhibition of SUMOylation may merit investigation as a possible therapy for Myc-driven human cancers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059214/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059214/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kessler, Jessica D -- Kahle, Kristopher T -- Sun, Tingting -- Meerbrey, Kristen L -- Schlabach, Michael R -- Schmitt, Earlene M -- Skinner, Samuel O -- Xu, Qikai -- Li, Mamie Z -- Hartman, Zachary C -- Rao, Mitchell -- Yu, Peng -- Dominguez-Vidana, Rocio -- Liang, Anthony C -- Solimini, Nicole L -- Bernardi, Ronald J -- Yu, Bing -- Hsu, Tiffany -- Golding, Ido -- Luo, Ji -- Osborne, C Kent -- Creighton, Chad J -- Hilsenbeck, Susan G -- Schiff, Rachel -- Shaw, Chad A -- Elledge, Stephen J -- Westbrook, Thomas F -- CA149196/CA/NCI NIH HHS/ -- P30 CA125123/CA/NCI NIH HHS/ -- P50 CA058183/CA/NCI NIH HHS/ -- R01 GM082837/GM/NIGMS NIH HHS/ -- R01GM082837/GM/NIGMS NIH HHS/ -- T32CA090221-09/CA/NCI NIH HHS/ -- T32HD05520/HD/NICHD NIH HHS/ -- U54 CA149196/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 Jan 20;335(6066):348-53. doi: 10.1126/science.1212728. Epub 2011 Dec 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22157079" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/*genetics/metabolism/mortality/pathology ; Cell Cycle ; Cell Line, Tumor ; *Cell Transformation, Neoplastic ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; *Genes, myc ; Humans ; Mammary Neoplasms, Experimental/genetics/metabolism/mortality/pathology ; Mice ; Mice, Nude ; Mitosis ; Neoplasm Transplantation ; Proto-Oncogene Proteins c-myc/*metabolism ; RNA Interference ; RNA, Small Interfering ; Spindle Apparatus/physiology ; Sumoylation ; *Transcription, Genetic ; Transplantation, Heterologous ; Ubiquitin-Activating Enzymes/antagonists & inhibitors/*genetics/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2016-02-26
    Description: 5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway. The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA-mediated screen across 390 cancer cell line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5. MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which we found to inhibit PRMT5 methyltransferase activity. Deletion of MTAP in MTAP-proficient cells rendered them sensitive to PRMT5 depletion. Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence. Thus, MTA accumulation in MTAP-deleted cancers creates a hypomorphic PRMT5 state that is selectively sensitized toward further PRMT5 inhibition. Inhibitors of PRMT5 that leverage this dysregulated metabolic state merit further investigation as a potential therapy for MTAP/CDKN2A-deleted tumors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mavrakis, Konstantinos J -- McDonald, E Robert 3rd -- Schlabach, Michael R -- Billy, Eric -- Hoffman, Gregory R -- deWeck, Antoine -- Ruddy, David A -- Venkatesan, Kavitha -- Yu, Jianjun -- McAllister, Gregg -- Stump, Mark -- deBeaumont, Rosalie -- Ho, Samuel -- Yue, Yingzi -- Liu, Yue -- Yan-Neale, Yan -- Yang, Guizhi -- Lin, Fallon -- Yin, Hong -- Gao, Hui -- Kipp, D Randal -- Zhao, Songping -- McNamara, Joshua T -- Sprague, Elizabeth R -- Zheng, Bing -- Lin, Ying -- Cho, Young Shin -- Gu, Justin -- Crawford, Kenneth -- Ciccone, David -- Vitari, Alberto C -- Lai, Albert -- Capka, Vladimir -- Hurov, Kristen -- Porter, Jeffery A -- Tallarico, John -- Mickanin, Craig -- Lees, Emma -- Pagliarini, Raymond -- Keen, Nicholas -- Schmelzle, Tobias -- Hofmann, Francesco -- Stegmeier, Frank -- Sellers, William R -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1208-13. doi: 10.1126/science.aad5944. Epub 2016 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. ; Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland. ; Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA. ; China Novartis Institutes for Biomedical Research, Shanghai 201203, China. ; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. william.sellers@novartis.com fstegmeier@ksqtx.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912361" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Cell Survival ; Cyclin-Dependent Kinase Inhibitor p16/genetics/*metabolism ; Deoxyadenosines/metabolism ; Gene Deletion ; Humans ; Methionine/*metabolism ; Neoplasms/drug therapy/genetics/*metabolism ; Protein-Arginine N-Methyltransferases/genetics/*metabolism ; Purine-Nucleoside Phosphorylase/genetics/*metabolism ; RNA, Small Interfering/genetics ; Thionucleosides/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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