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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)
    Details
    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
    Published by Nature Publishing Group (NPG)
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  • 2
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    Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-07-03
    Description: On activation by receptors, the ubiquitously expressed class IA isoforms (p110alpha and p110beta) of phosphatidylinositol-3-OH kinase (PI(3)K) generate lipid second messengers, which initiate multiple signal transduction cascades. Recent studies have demonstrated specific functions for p110alpha in growth factor and insulin signalling. To probe for distinct functions of p110beta, we constructed conditional knockout mice. Here we show that ablation of p110beta in the livers of the resulting mice leads to impaired insulin sensitivity and glucose homeostasis, while having little effect on phosphorylation of Akt, suggesting the involvement of a kinase-independent role of p110beta in insulin metabolic action. Using established mouse embryonic fibroblasts, we found that removal of p110beta also had little effect on Akt phosphorylation in response to stimulation by insulin and epidermal growth factor, but resulted in retarded cell proliferation. Reconstitution of p110beta-null cells with a wild-type or kinase-dead allele of p110beta demonstrated that p110beta possesses kinase-independent functions in regulating cell proliferation and trafficking. However, the kinase activity of p110beta was required for G-protein-coupled receptor signalling triggered by lysophosphatidic acid and had a function in oncogenic transformation. Most strikingly, in an animal model of prostate tumour formation induced by Pten loss, ablation of p110beta (also known as Pik3cb), but not that of p110alpha (also known as Pik3ca), impeded tumorigenesis with a concomitant diminution of Akt phosphorylation. Taken together, our findings demonstrate both kinase-dependent and kinase-independent functions for p110beta, and strongly indicate the kinase-dependent functions of p110beta as a promising target in cancer therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750091/" 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/PMC2750091/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jia, Shidong -- Liu, Zhenning -- Zhang, Sen -- Liu, Pixu -- Zhang, Lei -- Lee, Sang Hyun -- Zhang, Jing -- Signoretti, Sabina -- Loda, Massimo -- Roberts, Thomas M -- Zhao, Jean J -- P01 CA050661/CA/NCI NIH HHS/ -- P01 CA050661-200001/CA/NCI NIH HHS/ -- P01 CA089021/CA/NCI NIH HHS/ -- P01 CA089021-06A1/CA/NCI NIH HHS/ -- P50 CA089393/CA/NCI NIH HHS/ -- P50 CA089393-08S1/CA/NCI NIH HHS/ -- P50 CA090381/CA/NCI NIH HHS/ -- P50 CA090381-05/CA/NCI NIH HHS/ -- R01 CA030002/CA/NCI NIH HHS/ -- R01 CA030002-27/CA/NCI NIH HHS/ -- R01 CA134502/CA/NCI NIH HHS/ -- R01 CA134502-01/CA/NCI NIH HHS/ -- England -- Nature. 2008 Aug 7;454(7205):776-9. doi: 10.1038/nature07091. Epub 2008 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18594509" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Proliferation/drug effects ; *Cell Transformation, Neoplastic ; Epidermal Growth Factor/pharmacology ; Fibroblasts/cytology ; Glucose/*metabolism ; Glucose Intolerance/enzymology/genetics ; Homeostasis ; Humans ; Insulin/*metabolism/pharmacology ; Insulin Resistance/genetics ; Liver/enzymology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; PTEN Phosphohydrolase/deficiency/genetics ; Phosphatidylinositol 3-Kinases/deficiency/genetics/*metabolism ; Phosphorylation/drug effects ; Prostatic Neoplasms/enzymology/genetics/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction
    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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  • 3
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    Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-07-24
    Description: Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, beta-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signalling in medulloblastoma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413789/" 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/PMC3413789/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pugh, Trevor J -- Weeraratne, Shyamal Dilhan -- Archer, Tenley C -- Pomeranz Krummel, Daniel A -- Auclair, Daniel -- Bochicchio, James -- Carneiro, Mauricio O -- Carter, Scott L -- Cibulskis, Kristian -- Erlich, Rachel L -- Greulich, Heidi -- Lawrence, Michael S -- Lennon, Niall J -- McKenna, Aaron -- Meldrim, James -- Ramos, Alex H -- Ross, Michael G -- Russ, Carsten -- Shefler, Erica -- Sivachenko, Andrey -- Sogoloff, Brian -- Stojanov, Petar -- Tamayo, Pablo -- Mesirov, Jill P -- Amani, Vladimir -- Teider, Natalia -- Sengupta, Soma -- Francois, Jessica Pierre -- Northcott, Paul A -- Taylor, Michael D -- Yu, Furong -- Crabtree, Gerald R -- Kautzman, Amanda G -- Gabriel, Stacey B -- Getz, Gad -- Jager, Natalie -- Jones, David T W -- Lichter, Peter -- Pfister, Stefan M -- Roberts, Thomas M -- Meyerson, Matthew -- Pomeroy, Scott L -- Cho, Yoon-Jae -- CA050661/CA/NCI NIH HHS/ -- L40 NS063706/NS/NINDS NIH HHS/ -- P30 HD018655/HD/NICHD NIH HHS/ -- P30 HD18655/HD/NICHD NIH HHS/ -- R01 CA030002/CA/NCI NIH HHS/ -- R01 CA105607/CA/NCI NIH HHS/ -- R01 CA109467/CA/NCI NIH HHS/ -- R01 CA148699/CA/NCI NIH HHS/ -- R01 CA154480/CA/NCI NIH HHS/ -- R01 NS046789/NS/NINDS NIH HHS/ -- R01CA105607/CA/NCI NIH HHS/ -- R01CA109467/CA/NCI NIH HHS/ -- R01CA148699/CA/NCI NIH HHS/ -- R25 NS070682/NS/NINDS NIH HHS/ -- R25NS070682/NS/NINDS NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54HG003067/HG/NHGRI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Aug 2;488(7409):106-10. doi: 10.1038/nature11329.〈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/22820256" target="_blank"〉PubMed〈/a〉
    Keywords: Cerebellar Neoplasms/classification/*genetics ; Child ; DEAD-box RNA Helicases/chemistry/genetics/metabolism ; DNA Helicases/chemistry/genetics ; DNA-Binding Proteins/genetics ; Exome/*genetics ; Genome, Human/*genetics ; Hedgehog Proteins/metabolism ; Histone-Lysine N-Methyltransferase/genetics/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; LIM Domain Proteins/genetics ; Medulloblastoma/classification/*genetics ; Models, Molecular ; Mutation/*genetics ; Neoplasm Proteins/genetics ; Nuclear Proteins/chemistry/genetics ; Promoter Regions, Genetic/genetics ; Protein Structure, Tertiary/genetics ; Proto-Oncogene Proteins/genetics ; Receptors, Cell Surface/genetics ; Repressor Proteins/genetics ; Signal Transduction ; TCF Transcription Factors/metabolism ; Transcription Factors/chemistry/genetics ; Tumor Suppressor Protein p53/genetics ; Wnt Proteins/metabolism ; beta Catenin/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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  • 4
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    Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-07-14
    Description: X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability. Causal mutations have been found in approximately 90 X-linked genes; however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD (plant homeo domain) finger protein 8) is a JmjC domain-containing protein and its mutations have been found in patients with XLMR and craniofacial deformities. Here we provide multiple lines of evidence establishing PHF8 as the first mono-methyl histone H4 lysine 20 (H4K20me1) demethylase, with additional activities towards histone H3K9me1 and me2. PHF8 is located around the transcription start sites (TSS) of approximately 7,000 RefSeq genes and in gene bodies and intergenic regions (non-TSS). PHF8 depletion resulted in upregulation of H4K20me1 and H3K9me1 at the TSS and H3K9me2 in the non-TSS sites, respectively, demonstrating differential substrate specificities at different target locations. PHF8 positively regulates gene expression, which is dependent on its H3K4me3-binding PHD and catalytic domains. Importantly, patient mutations significantly compromised PHF8 catalytic function. PHF8 regulates cell survival in the zebrafish brain and jaw development, thus providing a potentially relevant biological context for understanding the clinical symptoms associated with PHF8 patients. Lastly, genetic and molecular evidence supports a model whereby PHF8 regulates zebrafish neuronal cell survival and jaw development in part by directly regulating the expression of the homeodomain transcription factor MSX1/MSXB, which functions downstream of multiple signalling and developmental pathways. Our findings indicate that an imbalance of histone methylation dynamics has a critical role in XLMR.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072215/" 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/PMC3072215/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qi, Hank H -- Sarkissian, Madathia -- Hu, Gang-Qing -- Wang, Zhibin -- Bhattacharjee, Arindam -- Gordon, D Benjamin -- Gonzales, Michelle -- Lan, Fei -- Ongusaha, Pat P -- Huarte, Maite -- Yaghi, Nasser K -- Lim, Huijun -- Garcia, Benjamin A -- Brizuela, Leonardo -- Zhao, Keji -- Roberts, Thomas M -- Shi, Yang -- GM 071004/GM/NIGMS NIH HHS/ -- NCI118487/PHS HHS/ -- P01CA50661/CA/NCI NIH HHS/ -- R01 GM071004/GM/NIGMS NIH HHS/ -- R01 GM071004-07/GM/NIGMS NIH HHS/ -- T32 CA09031-32/CA/NCI NIH HHS/ -- T32 NS007473/NS/NINDS NIH HHS/ -- England -- Nature. 2010 Jul 22;466(7305):503-7. doi: 10.1038/nature09261. Epub 2010 Jul 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20622853" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biocatalysis ; Brain/cytology/*embryology/*enzymology ; Catalytic Domain ; Cell Cycle ; Cell Line, Tumor ; Cell Survival ; DNA, Intergenic/genetics ; Gene Expression Regulation ; Head/*embryology ; Histone Demethylases/genetics/*metabolism ; Histones/chemistry/*metabolism ; Homeodomain Proteins/genetics ; Humans ; Jaw/cytology/embryology ; Lysine/metabolism ; Mental Retardation, X-Linked/enzymology/genetics ; Methylation ; Neurons/cytology/enzymology ; Promoter Regions, Genetic ; Transcription Factors/deficiency/genetics/*metabolism ; Transcription Initiation Site ; Zebrafish/*embryology/metabolism ; Zebrafish Proteins/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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  • 5
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    Corrigendum: Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-01-28
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jia, Shidong -- Liu, Zhenning -- Zhang, Sen -- Liu, Pixu -- Zhang, Lei -- Lee, Sang Hyun -- Zhang, Jing -- Signoretti, Sabina -- Loda, Massimo -- Roberts, Thomas M -- Zhao, Jean J -- England -- Nature. 2016 Jan 27;533(7602):278. doi: 10.1038/nature16543.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26814969" target="_blank"〉PubMed〈/a〉
    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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