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  • 1
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    COT drives resistance to RAF inhibition through MAP kinase pathway reactivation (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-11-26
    Description: Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed approximately 600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058384/" 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/PMC3058384/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Johannessen, Cory M -- Boehm, Jesse S -- Kim, So Young -- Thomas, Sapana R -- Wardwell, Leslie -- Johnson, Laura A -- Emery, Caroline M -- Stransky, Nicolas -- Cogdill, Alexandria P -- Barretina, Jordi -- Caponigro, Giordano -- Hieronymus, Haley -- Murray, Ryan R -- Salehi-Ashtiani, Kourosh -- Hill, David E -- Vidal, Marc -- Zhao, Jean J -- Yang, Xiaoping -- Alkan, Ozan -- Kim, Sungjoon -- Harris, Jennifer L -- Wilson, Christopher J -- Myer, Vic E -- Finan, Peter M -- Root, David E -- Roberts, Thomas M -- Golub, Todd -- Flaherty, Keith T -- Dummer, Reinhard -- Weber, Barbara L -- Sellers, William R -- Schlegel, Robert -- Wargo, Jennifer A -- Hahn, William C -- Garraway, Levi A -- CA134502/CA/NCI NIH HHS/ -- DP2 OD002750/OD/NIH HHS/ -- DP2 OD002750-01/OD/NIH HHS/ -- K08 CA115927/CA/NCI NIH HHS/ -- K08 CA115927-05/CA/NCI NIH HHS/ -- P50 CA093683/CA/NCI NIH HHS/ -- R01 CA134502/CA/NCI NIH HHS/ -- R33 CA128625/CA/NCI NIH HHS/ -- RC2 CA148268/CA/NCI NIH HHS/ -- England -- Nature. 2010 Dec 16;468(7326):968-72. doi: 10.1038/nature09627. Epub 2010 Nov 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21107320" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Cell Line, Tumor ; Clinical Trials as Topic ; *Drug Resistance, Neoplasm/drug effects/genetics ; Enzyme Activation/drug effects ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Library ; Humans ; Indoles/pharmacology/therapeutic use ; MAP Kinase Kinase Kinases/genetics/*metabolism ; *MAP Kinase Signaling System ; Melanoma/drug therapy/enzymology/genetics/metabolism ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Open Reading Frames/genetics ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; Proto-Oncogene Proteins/genetics/*metabolism ; Proto-Oncogene Proteins B-raf/*antagonists & ; inhibitors/chemistry/genetics/metabolism ; Proto-Oncogene Proteins c-raf/genetics/metabolism ; Sulfonamides/pharmacology/therapeutic use
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Identification of RPS14 as a 5q- syndrome gene by RNA interference screen (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-01-19
    Description: Somatic chromosomal deletions in cancer are thought to indicate the location of tumour suppressor genes, by which a complete loss of gene function occurs through biallelic deletion, point mutation or epigenetic silencing, thus fulfilling Knudson's two-hit hypothesis. In many recurrent deletions, however, such biallelic inactivation has not been found. One prominent example is the 5q- syndrome, a subtype of myelodysplastic syndrome characterized by a defect in erythroid differentiation. Here we describe an RNA-mediated interference (RNAi)-based approach to discovery of the 5q- disease gene. We found that partial loss of function of the ribosomal subunit protein RPS14 phenocopies the disease in normal haematopoietic progenitor cells, and also that forced expression of RPS14 rescues the disease phenotype in patient-derived bone marrow cells. In addition, we identified a block in the processing of pre-ribosomal RNA in RPS14-deficient cells that is functionally equivalent to the defect in Diamond-Blackfan anaemia, linking the molecular pathophysiology of the 5q- syndrome to a congenital syndrome causing bone marrow failure. These results indicate that the 5q- syndrome is caused by a defect in ribosomal protein function and suggest that RNAi screening is an effective strategy for identifying causal haploinsufficiency disease genes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771855/" 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/PMC3771855/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ebert, Benjamin L -- Pretz, Jennifer -- Bosco, Jocelyn -- Chang, Cindy Y -- Tamayo, Pablo -- Galili, Naomi -- Raza, Azra -- Root, David E -- Attar, Eyal -- Ellis, Steven R -- Golub, Todd R -- R01 HL082945/HL/NHLBI NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Jan 17;451(7176):335-9. doi: 10.1038/nature06494.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18202658" target="_blank"〉PubMed〈/a〉
    Keywords: Anemia, Diamond-Blackfan/genetics/physiopathology ; Cell Differentiation ; Cells, Cultured ; Chromosome Deletion ; Chromosomes, Human, Pair 5/*genetics ; Erythroid Cells/cytology/metabolism ; Genetic Linkage/*genetics ; Genetic Predisposition to Disease/*genetics ; Hematopoietic Stem Cells/metabolism ; Humans ; Phenotype ; *RNA Interference ; RNA Precursors/genetics/metabolism ; RNA, Ribosomal/genetics/metabolism ; RNA, Ribosomal, 18S/genetics ; Ribosomal Proteins/deficiency/*genetics/metabolism ; Ribosomes/chemistry/genetics/metabolism ; Syndrome
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-09-17
    Description: Aberrant activation of the canonical WNT/beta-catenin pathway occurs in almost all colorectal cancers and contributes to their growth, invasion and survival. Although dysregulated beta-catenin activity drives colon tumorigenesis, further genetic perturbations are required to elaborate full malignant transformation. To identify genes that both modulate beta-catenin activity and are essential for colon cancer cell proliferation, we conducted two loss-of-function screens in human colon cancer cells and compared genes identified in these screens with an analysis of copy number alterations in colon cancer specimens. One of these genes, CDK8, which encodes a member of the mediator complex, is located at 13q12.13, a region of recurrent copy number gain in a substantial fraction of colon cancers. Here we show that the suppression of CDK8 expression inhibits proliferation in colon cancer cells characterized by high levels of CDK8 and beta-catenin hyperactivity. CDK8 kinase activity was necessary for beta-catenin-driven transformation and for expression of several beta-catenin transcriptional targets. Together these observations suggest that therapeutic interventions targeting CDK8 may confer a clinical benefit in beta-catenin-driven malignancies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587138/" 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/PMC2587138/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Firestein, Ron -- Bass, Adam J -- Kim, So Young -- Dunn, Ian F -- Silver, Serena J -- Guney, Isil -- Freed, Ellen -- Ligon, Azra H -- Vena, Natalie -- Ogino, Shuji -- Chheda, Milan G -- Tamayo, Pablo -- Finn, Stephen -- Shrestha, Yashaswi -- Boehm, Jesse S -- Jain, Supriya -- Bojarski, Emeric -- Mermel, Craig -- Barretina, Jordi -- Chan, Jennifer A -- Baselga, Jose -- Tabernero, Josep -- Root, David E -- Fuchs, Charles S -- Loda, Massimo -- Shivdasani, Ramesh A -- Meyerson, Matthew -- Hahn, William C -- K08 CA134931/CA/NCI NIH HHS/ -- P50CA127003/CA/NCI NIH HHS/ -- R33 CA128625/CA/NCI NIH HHS/ -- R33 CA128625-01A1/CA/NCI NIH HHS/ -- R33CA128625/CA/NCI NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Sep 25;455(7212):547-51. doi: 10.1038/nature07179. Epub 2008 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18794900" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic ; Colorectal Neoplasms/*genetics/*metabolism/pathology ; Cyclin-Dependent Kinase 8 ; Cyclin-Dependent Kinases/deficiency/*genetics/*metabolism ; Gene Dosage ; *Gene Expression Regulation, Neoplastic ; Humans ; Oncogene Proteins/deficiency/genetics/metabolism ; *Oncogenes ; RNA Interference ; Transcription, Genetic ; beta Catenin/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-10-23
    Description: The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. A complementary strategy for targeting KRAS is to identify gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkappaB kinase TBK1 was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving c-Rel and BCL-XL (also known as BCL2L1) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations indicate that TBK1 and NF-kappaB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2783335/" 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/PMC2783335/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barbie, David A -- Tamayo, Pablo -- Boehm, Jesse S -- Kim, So Young -- Moody, Susan E -- Dunn, Ian F -- Schinzel, Anna C -- Sandy, Peter -- Meylan, Etienne -- Scholl, Claudia -- Frohling, Stefan -- Chan, Edmond M -- Sos, Martin L -- Michel, Kathrin -- Mermel, Craig -- Silver, Serena J -- Weir, Barbara A -- Reiling, Jan H -- Sheng, Qing -- Gupta, Piyush B -- Wadlow, Raymond C -- Le, Hanh -- Hoersch, Sebastian -- Wittner, Ben S -- Ramaswamy, Sridhar -- Livingston, David M -- Sabatini, David M -- Meyerson, Matthew -- Thomas, Roman K -- Lander, Eric S -- Mesirov, Jill P -- Root, David E -- Gilliland, D Gary -- Jacks, Tyler -- Hahn, William C -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA129105-03/CA/NCI NIH HHS/ -- R01 CA130988/CA/NCI NIH HHS/ -- R01 CA130988-01A2/CA/NCI NIH HHS/ -- R33 CA128625/CA/NCI NIH HHS/ -- R33 CA128625-01A1/CA/NCI NIH HHS/ -- R33 CA128625-02/CA/NCI NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- T32 CA09172-33/CA/NCI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Nov 5;462(7269):108-12. doi: 10.1038/nature08460. Epub 2009 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115 USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847166" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Apoptosis ; Cell Line, Tumor ; Cell Survival ; Gene Expression Profiling ; Genes, Lethal ; Genes, ras/*genetics ; Humans ; Lung Neoplasms/genetics/metabolism/pathology ; Neoplasms/genetics/metabolism/pathology ; Oncogene Protein p21(ras)/*genetics/*metabolism ; Protein-Serine-Threonine Kinases/antagonists & inhibitors/*metabolism ; Proto-Oncogene Proteins c-rel/metabolism ; *RNA Interference ; Signal Transduction ; bcl-X Protein/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-02-09
    Description: Mutations in IDH1 and IDH2, the genes coding for isocitrate dehydrogenases 1 and 2, are common in several human cancers, including leukemias, and result in overproduction of the (R)-enantiomer of 2-hydroxyglutarate [(R)-2HG]. Elucidation of the role of IDH mutations and (R)-2HG in leukemogenesis has been hampered by a lack of appropriate cell-based models. Here, we show that a canonical IDH1 mutant, IDH1 R132H, promotes cytokine independence and blocks differentiation in hematopoietic cells. These effects can be recapitulated by (R)-2HG, but not (S)-2HG, despite the fact that (S)-2HG more potently inhibits enzymes, such as the 5'-methylcytosine hydroxylase TET2, that have previously been linked to the pathogenesis of IDH mutant tumors. We provide evidence that this paradox relates to the ability of (S)-2HG, but not (R)-2HG, to inhibit the EglN prolyl hydroxylases. Additionally, we show that transformation by (R)-2HG is reversible.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836459/" 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/PMC3836459/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Losman, Julie-Aurore -- Looper, Ryan E -- Koivunen, Peppi -- Lee, Sungwoo -- Schneider, Rebekka K -- McMahon, Christine -- Cowley, Glenn S -- Root, David E -- Ebert, Benjamin L -- Kaelin, William G Jr -- P30 DK049216/DK/NIDDK NIH HHS/ -- R01 CA068490/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Mar 29;339(6127):1621-5. doi: 10.1126/science.1231677. Epub 2013 Feb 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23393090" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/*metabolism ; Glutarates/*metabolism ; *Hematopoiesis ; Humans ; Isocitrate Dehydrogenase/genetics/*metabolism ; Leukemia/*enzymology/genetics ; Models, Biological ; Procollagen-Proline Dioxygenase/*antagonists & inhibitors
    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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  • 6
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    Functional genomics reveal that the serine synthesis pathway is essential in breast cancer (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-07-16
    Description: Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation. RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes. Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers. PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of alpha-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353325/" 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/PMC3353325/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Possemato, Richard -- Marks, Kevin M -- Shaul, Yoav D -- Pacold, Michael E -- Kim, Dohoon -- Birsoy, Kivanc -- Sethumadhavan, Shalini -- Woo, Hin-Koon -- Jang, Hyun G -- Jha, Abhishek K -- Chen, Walter W -- Barrett, Francesca G -- Stransky, Nicolas -- Tsun, Zhi-Yang -- Cowley, Glenn S -- Barretina, Jordi -- Kalaany, Nada Y -- Hsu, Peggy P -- Ottina, Kathleen -- Chan, Albert M -- Yuan, Bingbing -- Garraway, Levi A -- Root, David E -- Mino-Kenudson, Mari -- Brachtel, Elena F -- Driggers, Edward M -- Sabatini, David M -- CA103866/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA103866-06A1/CA/NCI NIH HHS/ -- R01 CA103866-07/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA129105-02/CA/NCI NIH HHS/ -- R01 CA129105-05/CA/NCI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Aug 18;476(7360):346-50. doi: 10.1038/nature10350.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21760589" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomarkers, Tumor/metabolism ; Breast Neoplasms/enzymology/*genetics/*metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation ; Citric Acid Cycle/physiology ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; *Genomics ; Glutamic Acid/metabolism ; Humans ; Ketoglutaric Acids/metabolism ; Melanoma/enzymology/genetics ; Mice ; Neoplasm Transplantation ; Phosphoglycerate Dehydrogenase/genetics/metabolism ; RNA Interference ; Serine/*biosynthesis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    lincRNAs act in the circuitry controlling pluripotency and differentiation (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-08-30
    Description: Although thousands of large intergenic non-coding RNAs (lincRNAs) have been identified in mammals, few have been functionally characterized, leading to debate about their biological role. To address this, we performed loss-of-function studies on most lincRNAs expressed in mouse embryonic stem (ES) cells and characterized the effects on gene expression. Here we show that knockdown of lincRNAs has major consequences on gene expression patterns, comparable to knockdown of well-known ES cell regulators. Notably, lincRNAs primarily affect gene expression in trans. Knockdown of dozens of lincRNAs causes either exit from the pluripotent state or upregulation of lineage commitment programs. We integrate lincRNAs into the molecular circuitry of ES cells and show that lincRNA genes are regulated by key transcription factors and that lincRNA transcripts bind to multiple chromatin regulatory proteins to affect shared gene expression programs. Together, the results demonstrate that lincRNAs have key roles in the circuitry controlling ES cell state.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175327/" 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/PMC3175327/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guttman, Mitchell -- Donaghey, Julie -- Carey, Bryce W -- Garber, Manuel -- Grenier, Jennifer K -- Munson, Glen -- Young, Geneva -- Lucas, Anne Bergstrom -- Ach, Robert -- Bruhn, Laurakay -- Yang, Xiaoping -- Amit, Ido -- Meissner, Alexander -- Regev, Aviv -- Rinn, John L -- Root, David E -- Lander, Eric S -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003067-09/HG/NHGRI NIH HHS/ -- England -- Nature. 2011 Aug 28;477(7364):295-300. doi: 10.1038/nature10398.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. mguttman@mit.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21874018" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation/*genetics ; Cell Lineage/genetics ; Chromatin/genetics/metabolism ; Gene Expression Regulation/genetics ; Gene Knockdown Techniques ; Mice ; Pluripotent Stem Cells/*cytology/*metabolism ; Protein Binding ; RNA, Untranslated/*genetics/*metabolism ; Transcription Factors/metabolism
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  • 8
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    In vivo discovery of immunotherapy targets in the tumour microenvironment (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-01-31
    Description: Recent clinical trials showed that targeting of inhibitory receptors on T cells induces durable responses in a subset of cancer patients, despite advanced disease. However, the regulatory switches controlling T-cell function in immunosuppressive tumours are not well understood. Here we show that such inhibitory mechanisms can be systematically discovered in the tumour microenvironment. We devised an in vivo pooled short hairpin RNA (shRNA) screen in which shRNAs targeting negative regulators became highly enriched in murine tumours by releasing a block on T-cell proliferation upon tumour antigen recognition. Such shRNAs were identified by deep sequencing of the shRNA cassette from T cells infiltrating tumour or control tissues. One of the target genes was Ppp2r2d, a regulatory subunit of the PP2A phosphatase family. In tumours, Ppp2r2d knockdown inhibited T-cell apoptosis and enhanced T-cell proliferation as well as cytokine production. Key regulators of immune function can therefore be discovered in relevant tissue microenvironments.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052214/" 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/PMC4052214/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Penghui -- Shaffer, Donald R -- Alvarez Arias, Diana A -- Nakazaki, Yukoh -- Pos, Wouter -- Torres, Alexis J -- Cremasco, Viviana -- Dougan, Stephanie K -- Cowley, Glenn S -- Elpek, Kutlu -- Brogdon, Jennifer -- Lamb, John -- Turley, Shannon J -- Ploegh, Hidde L -- Root, David E -- Love, J Christopher -- Dranoff, Glenn -- Hacohen, Nir -- Cantor, Harvey -- Wucherpfennig, Kai W -- 1R01CA173750/CA/NCI NIH HHS/ -- DP3 DK097681/DK/NIDDK NIH HHS/ -- P01 AI045757/AI/NIAID NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R01 CA173750/CA/NCI NIH HHS/ -- T32 AI007386/AI/NIAID NIH HHS/ -- T32 AI07386/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Feb 6;506(7486):52-7. doi: 10.1038/nature12988. Epub 2014 Jan 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2]. ; 1] Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] [3] Jounce Therapeutics, Cambridge, Massachusetts 02138, USA. ; Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. ; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; Whitehead Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; 1] Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Jounce Therapeutics, Cambridge, Massachusetts 02138, USA. ; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA. ; Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24476824" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Neoplasm/immunology ; Apoptosis/immunology ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/cytology/immunology/secretion ; Cell Proliferation ; Cytokines/immunology/secretion ; Female ; Gene Knockdown Techniques ; High-Throughput Nucleotide Sequencing ; *Immunotherapy/methods ; Lymphocytes, Tumor-Infiltrating/cytology/immunology/metabolism/secretion ; Melanoma, Experimental/immunology ; Mice ; Mice, Inbred C57BL ; *Molecular Targeted Therapy ; Protein Phosphatase 2/deficiency/genetics/*metabolism ; RNA, Small Interfering/genetics ; Reproducibility of Results ; Tumor Microenvironment/*immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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    The bromodomain protein Brd4 insulates chromatin from DNA damage signalling (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-06-04
    Description: DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683358/" 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/PMC3683358/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Floyd, Scott R -- Pacold, Michael E -- Huang, Qiuying -- Clarke, Scott M -- Lam, Fred C -- Cannell, Ian G -- Bryson, Bryan D -- Rameseder, Jonathan -- Lee, Michael J -- Blake, Emily J -- Fydrych, Anna -- Ho, Richard -- Greenberger, Benjamin A -- Chen, Grace C -- Maffa, Amanda -- Del Rosario, Amanda M -- Root, David E -- Carpenter, Anne E -- Hahn, William C -- Sabatini, David M -- Chen, Clark C -- White, Forest M -- Bradner, James E -- Yaffe, Michael B -- 1-U54-CA112967-04/CA/NCI NIH HHS/ -- ES-002109/ES/NIEHS NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30 ES002109/ES/NIEHS NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R01 ES015339/ES/NIEHS NIH HHS/ -- R01-ES15339/ES/NIEHS NIH HHS/ -- R21 CA109661/CA/NCI NIH HHS/ -- R21 NS063917/NS/NINDS NIH HHS/ -- R21-NS063917/NS/NINDS NIH HHS/ -- U54 CA112967/CA/NCI NIH HHS/ -- England -- Nature. 2013 Jun 13;498(7453):246-50. doi: 10.1038/nature12147. Epub 2013 Jun 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23728299" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Adenosine Triphosphatases/metabolism ; Cell Cycle Checkpoints/radiation effects ; Cell Line, Tumor ; Cell Survival/radiation effects ; Chromatin/chemistry/*metabolism/radiation effects ; *Chromatin Assembly and Disassembly/radiation effects ; *DNA Damage ; DNA Repair/radiation effects ; DNA-Binding Proteins/metabolism ; Histones/chemistry/metabolism ; Humans ; Lysine/chemistry/metabolism ; Multiprotein Complexes/metabolism ; Nuclear Proteins/chemistry/deficiency/genetics/*metabolism ; Phosphorylation/radiation effects ; Positive Transcriptional Elongation Factor B/metabolism ; Protein Isoforms/metabolism ; Radiation, Ionizing ; *Signal Transduction/radiation effects ; Transcription Factors/chemistry/deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    A melanocyte lineage program confers resistance to MAP kinase pathway inhibition (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-11-05
    Description: Malignant melanomas harbouring point mutations (Val600Glu) in the serine/threonine-protein kinase BRAF (BRAF(V600E)) depend on RAF-MEK-ERK signalling for tumour cell growth. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma; however, resistance to these agents remains a formidable challenge. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here we carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF-MEK inhibitors. These studies revealed a cyclic-AMP-dependent melanocytic signalling network not previously associated with drug resistance, including G-protein-coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF-MEK inhibition but restored in relapsing tumours. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAPK-pathway and histone-deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF-MEK-ERK inhibition, which may be overcome by combining signalling- and chromatin-directed therapeutics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098832/" 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/PMC4098832/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Johannessen, Cory M -- Johnson, Laura A -- Piccioni, Federica -- Townes, Aisha -- Frederick, Dennie T -- Donahue, Melanie K -- Narayan, Rajiv -- Flaherty, Keith T -- Wargo, Jennifer A -- Root, David E -- Garraway, Levi A -- DP2 OD002750/OD/NIH HHS/ -- DP2OD002750/OD/NIH HHS/ -- P01 CA163222/CA/NCI NIH HHS/ -- P50CA93683/CA/NCI NIH HHS/ -- R33 CA155554/CA/NCI NIH HHS/ -- U01 HG006492/HG/NHGRI NIH HHS/ -- U54 CA112962/CA/NCI NIH HHS/ -- U54 HG006093/HG/NHGRI NIH HHS/ -- England -- Nature. 2013 Dec 5;504(7478):138-42. doi: 10.1038/nature12688. Epub 2013 Nov 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] The Broad Institute of Harvard University and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA [3] Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24185007" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Agents/*pharmacology ; CREB-Binding Protein/metabolism ; Cell Line, Tumor ; Cell Lineage ; Cyclic AMP/metabolism ; Drug Resistance, Neoplasm/*genetics ; Gene Expression Regulation, Neoplastic ; HEK293 Cells ; Humans ; Melanocytes/cytology/*drug effects/enzymology ; Melanoma/enzymology/physiopathology ; Mitogen-Activated Protein Kinases/*metabolism ; Protein Kinase Inhibitors/*pharmacology ; Signal Transduction ; Transcription Factors/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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