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  • 1
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    14-3-3 fusion oncogenes in high-grade endometrial stromal sarcoma [Medical Sciences] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-01-18
    Description: 14-3-3 proteins are ubiquitously expressed regulators of various cellular functions, including proliferation, metabolism, and differentiation, and altered 14-3-3 expression is associated with development and progression of cancer. We report a transforming 14-3-3 oncoprotein, which we identified through conventional cytogenetics and whole-transcriptome sequencing analysis as a highly recurrent genetic mechanism in a clinically aggressive form of uterine sarcoma: high-grade endometrial stromal sarcoma (ESS). The 14-3-3 oncoprotein results from a t(10;17) genomic rearrangement, leading to fusion between 14-3-3ε (YWHAE) and either of two nearly identical FAM22 family members (FAM22A or FAM22B). Expression of YWHAE–FAM22 fusion oncoproteins was demonstrated by immunoblot in t(10;17)-bearing frozen tumor and cell line samples. YWHAE–FAM22 fusion gene knockdowns were performed with shRNAs and siRNAs targeting various FAM22A exons in an t(10;17)-bearing ESS cell line (ESS1): Fusion protein expression was inhibited, with corresponding reduction in cell growth and migration. YWHAE–FAM22 maintains a structurally and functionally intact 14-3-3ε (YWHAE) protein-binding domain, which is directed to the nucleus by a FAM22 nuclear localization sequence. In contrast to classic ESS, harboring JAZF1 genetic fusions, YWHAE–FAM22 ESS display high-grade histologic features, a distinct gene-expression profile, and a more aggressive clinical course. Fluorescence in situ hybridization analysis demonstrated absolute specificity of YWHAE–FAM22A/B genetic rearrangement for high-grade ESS, with no fusions detected in other uterine and nonuterine mesenchymal tumors (55 tumor types, n = 827). These discoveries reveal diagnostically and therapeutically relevant models for characterizing aberrant 14-3-3 oncogenic functions.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-09-25
    Description: The flow of information from calcium-mobilizing receptors to nuclear factor of activated T cells (NFAT)-dependent genes is critically dependent on interaction between the phosphatase calcineurin and the transcription factor NFAT. A high-affinity calcineurin-binding peptide was selected from combinatorial peptide libraries based on the calcineurin docking motif of NFAT. This peptide potently inhibited NFAT activation and NFAT-dependent expression of endogenous cytokine genes in T cells, without affecting the expression of other cytokines that require calcineurin but not NFAT. Substitution of the optimized peptide sequence into the natural calcineurin docking site increased the calcineurin responsiveness of NFAT. Compounds that interfere selectively with the calcineurin-NFAT interaction without affecting calcineurin phosphatase activity may be useful as therapeutic agents that are less toxic than current drugs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Aramburu, J -- Yaffe, M B -- Lopez-Rodriguez, C -- Cantley, L C -- Hogan, P G -- Rao, A -- R01 AI 40127/AI/NIAID NIH HHS/ -- R01 GM056203/GM/NIGMS NIH HHS/ -- R01 HL 03601/HL/NHLBI NIH HHS/ -- R43 AI 43726/AI/NIAID NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1999 Sep 24;285(5436):2129-33.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10497131" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding Sites ; Calcineurin/*metabolism ; Calcineurin Inhibitors ; Cell Nucleus/metabolism ; Cyclosporine/pharmacology ; Cytokines/biosynthesis/genetics ; DNA-Binding Proteins/*antagonists & inhibitors/chemistry/metabolism ; Gene Expression Regulation ; Genes, Reporter ; HeLa Cells ; Humans ; Immunosuppressive Agents/chemistry/metabolism/*pharmacology ; Jurkat Cells ; Molecular Sequence Data ; NFATC Transcription Factors ; *Nuclear Proteins ; Oligopeptides/chemistry/metabolism/*pharmacology ; Peptide Library ; Peptides/chemistry/metabolism/*pharmacology ; Phosphorylation ; Recombinant Fusion Proteins/metabolism ; T-Lymphocytes/*drug effects/immunology ; Transcription Factors/*antagonists & inhibitors/chemistry/metabolism ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism (1998)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1998-01-07
    Description: Pin1 is an essential and conserved mitotic peptidyl-prolyl isomerase (PPIase) that is distinct from members of two other families of conventional PPIases, cyclophilins and FKBPs (FK-506 binding proteins). In response to their phosphorylation during mitosis, Pin1 binds and regulates members of a highly conserved set of proteins that overlaps with antigens recognized by the mitosis-specific monoclonal antibody MPM-2. Pin1 is here shown to be a phosphorylation-dependent PPIase that specifically recognizes the phosphoserine-proline or phosphothreonine-proline bonds present in mitotic phosphoproteins. Both Pin1 and MPM-2 selected similar phosphorylated serine-proline-containing peptides, providing the basis for the specific interaction between Pin1 and MPM-2 antigens. Pin1 preferentially isomerized proline residues preceded by phosphorylated serine or threonine with up to 1300-fold selectivity compared with unphosphorylated peptides. Pin1 may thus regulate mitotic progression by catalyzing sequence-specific and phosphorylation-dependent proline isomerization.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yaffe, M B -- Schutkowski, M -- Shen, M -- Zhou, X Z -- Stukenberg, P T -- Rahfeld, J U -- Xu, J -- Kuang, J -- Kirschner, M W -- Fischer, G -- Cantley, L C -- Lu, K P -- GM56203/GM/NIGMS NIH HHS/ -- GM56230/GM/NIGMS NIH HHS/ -- R01 GM056203/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1997 Dec 12;278(5345):1957-60.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9395400" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Isomerases/metabolism ; Antibodies, Monoclonal ; Binding Sites ; Carrier Proteins/metabolism ; Cell Cycle Proteins/chemistry/*metabolism ; DNA-Binding Proteins/metabolism ; Epitopes ; HeLa Cells ; Heat-Shock Proteins/metabolism ; Humans ; Isomerism ; *Mitosis ; Models, Molecular ; Oligopeptides/chemistry/*metabolism ; Peptide Library ; Peptidylprolyl Isomerase/chemistry/*metabolism ; Phosphoproteins/chemistry/immunology/*metabolism ; Phosphorylation ; Phosphoserine/metabolism ; Phosphothreonine/metabolism ; Proline/*metabolism ; Protein Conformation ; Recombinant Fusion Proteins/chemistry/metabolism ; Substrate Specificity ; Tacrolimus Binding Proteins
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-07-11
    Description: Polo-like kinase-1 (PLK1) is an essential mitotic kinase regulating multiple aspects of the cell division process. Activation of PLK1 requires phosphorylation of a conserved threonine residue (Thr 210) in the T-loop of the PLK1 kinase domain, but the kinase responsible for this has not yet been affirmatively identified. Here we show that in human cells PLK1 activation occurs several hours before entry into mitosis, and requires aurora A (AURKA, also known as STK6)-dependent phosphorylation of Thr 210. We find that aurora A can directly phosphorylate PLK1 on Thr 210, and that activity of aurora A towards PLK1 is greatly enhanced by Bora (also known as C13orf34 and FLJ22624), a known cofactor for aurora A (ref. 7). We show that Bora/aurora-A-dependent phosphorylation is a prerequisite for PLK1 to promote mitotic entry after a checkpoint-dependent arrest. Importantly, expression of a PLK1-T210D phospho-mimicking mutant partially overcomes the requirement for aurora A in checkpoint recovery. Taken together, these data demonstrate that the initial activation of PLK1 is a primary function of aurora A.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Macurek, Libor -- Lindqvist, Arne -- Lim, Dan -- Lampson, Michael A -- Klompmaker, Rob -- Freire, Raimundo -- Clouin, Christophe -- Taylor, Stephen S -- Yaffe, Michael B -- Medema, Rene H -- CA112967/CA/NCI NIH HHS/ -- GM-60594/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Sep 4;455(7209):119-23. doi: 10.1038/nature07185. Epub 2008 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18615013" target="_blank"〉PubMed〈/a〉
    Keywords: Aurora Kinase A ; Aurora Kinases ; Cell Cycle/*physiology ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line ; DNA Damage ; Enzyme Activation ; Humans ; Mitosis ; Molecular Sequence Data ; Phosphorylation ; Phosphothreonine/metabolism ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; Proto-Oncogene Proteins/genetics/*metabolism ; Time Factors
    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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  • 5
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    Activation of the yeast Hippo pathway by phosphorylation-dependent assembly of signaling complexes (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-04-13
    Description: Scaffold-assisted signaling cascades guide cellular decision-making. In budding yeast, one such signal transduction pathway called the mitotic exit network (MEN) governs the transition from mitosis to the G1 phase of the cell cycle. The MEN is conserved and in metazoans is known as the Hippo tumor-suppressor pathway. We found that signaling through the MEN kinase cascade was mediated by an unusual two-step process. The MEN kinase Cdc15 first phosphorylated the scaffold Nud1. This created a phospho-docking site on Nud1, to which the effector kinase complex Dbf2-Mob1 bound through a phosphoserine-threonine binding domain, in order to be activated by Cdc15. This mechanism of pathway activation has implications for signal transmission through other kinase cascades and might represent a general principle in scaffold-assisted signaling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884217/" 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/PMC3884217/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rock, Jeremy M -- Lim, Daniel -- Stach, Lasse -- Ogrodowicz, Roksana W -- Keck, Jamie M -- Jones, Michele H -- Wong, Catherine C L -- Yates, John R 3rd -- Winey, Mark -- Smerdon, Stephen J -- Yaffe, Michael B -- Amon, Angelika -- CA112967/CA/NCI NIH HHS/ -- ES015339/ES/NIEHS NIH HHS/ -- F32 GM086038/GM/NIGMS NIH HHS/ -- GM056800/GM/NIGMS NIH HHS/ -- GM51312/GM/NIGMS NIH HHS/ -- MC_U117584228/Medical Research Council/United Kingdom -- P30 CA014051/CA/NCI NIH HHS/ -- P41 GM103533/GM/NIGMS NIH HHS/ -- P41 RR011823/RR/NCRR NIH HHS/ -- R01 ES015339/ES/NIEHS NIH HHS/ -- R01 GM051312/GM/NIGMS NIH HHS/ -- R01 GM056800/GM/NIGMS NIH HHS/ -- R29 GM056800/GM/NIGMS NIH HHS/ -- U117584228/Medical Research Council/United Kingdom -- U54 CA112967/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 May 17;340(6134):871-5. doi: 10.1126/science.1235822. Epub 2013 Apr 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23579499" target="_blank"〉PubMed〈/a〉
    Keywords: Anaphase ; Cell Cycle Proteins/chemistry/*metabolism ; Deoxyribonucleases/chemistry/*metabolism ; Enzyme Activation ; GTP-Binding Proteins/*metabolism ; *Mitosis ; Phosphoproteins/chemistry/*metabolism ; Phosphorylation ; Protein Conformation ; Protein-Serine-Threonine Kinases/*metabolism ; Saccharomyces cerevisiae/cytology/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Signal Transduction ; tRNA Methyltransferases/chemistry/*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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  • 6
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    Proteomic screen finds pSer/pThr-binding domain localizing Plk1 to mitotic substrates (2003)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2003-02-22
    Description: We have developed a proteomic approach for identifying phosphopeptide binding domains that modulate kinase-dependent signaling pathways. An immobilized library of partially degenerate phosphopeptides biased toward a particular protein kinase phosphorylation motif is used to isolate phospho-binding domains that bind to proteins phosphorylated by that kinase. Applying this approach to cyclin-dependent kinases (Cdks), we identified the polo-box domain (PBD) of the mitotic kinase polo-like kinase 1 (Plk1) as a specific phosphoserine (pSer) or phosphothreonine (pThr) binding domain and determined its optimal binding motif. This motif is present in known Plk1 substrates such as Cdc25, and an optimal phosphopeptide containing the motif disrupted PBD-substrate binding and localization of the PBD to centrosomes. This finding reveals how Plk1 can localize to specific sites within cells in response to Cdk phosphorylation at those sites and provides a structural mechanism for targeting the Plk1 kinase domain to its substrates.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Elia, Andrew E H -- Cantley, Lewis C -- Yaffe, Michael B -- GM52981/GM/NIGMS NIH HHS/ -- GM56203/GM/NIGMS NIH HHS/ -- R01 GM056203/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2003 Feb 21;299(5610):1228-31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12595692" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Binding Sites ; Calorimetry ; Cell Cycle Proteins ; Centrosome/metabolism ; HeLa Cells ; Humans ; Ligands ; Mitosis ; Peptide Library ; Phosphopeptides/chemistry/*metabolism ; Phosphorylation ; Phosphoserine/*metabolism ; Phosphothreonine/*metabolism ; Point Mutation ; Protein Binding ; Protein Kinases/*chemistry/genetics/*metabolism ; *Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases ; Proteomics ; Proto-Oncogene Proteins ; Signal Transduction ; cdc25 Phosphatases/chemistry/genetics/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 7
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    TAZ, a transcriptional modulator of mesenchymal stem cell differentiation (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-08-16
    Description: Mesenchymal stem cells (MSCs) are a pluripotent cell type that can differentiate into several distinct lineages. Two key transcription factors, Runx2 and peroxisome proliferator-activated receptor gamma (PPARgamma), drive MSCs to differentiate into either osteoblasts or adipocytes, respectively. How these two transcription factors are regulated in order to specify these alternate cell fates remains a pivotal question. Here we report that a 14-3-3-binding protein, TAZ (transcriptional coactivator with PDZ-binding motif), coactivates Runx2-dependent gene transcription while repressing PPARgamma-dependent gene transcription. By modulating TAZ expression in model cell lines, mouse embryonic fibroblasts, and primary MSCs in culture and in zebrafish in vivo, we observed alterations in osteogenic versus adipogenic potential. These results indicate that TAZ functions as a molecular rheostat that modulates MSC differentiation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hong, Jeong-Ho -- Hwang, Eun Sook -- McManus, Michael T -- Amsterdam, Adam -- Tian, Yu -- Kalmukova, Ralitsa -- Mueller, Elisabetta -- Benjamin, Thomas -- Spiegelman, Bruce M -- Sharp, Phillip A -- Hopkins, Nancy -- Yaffe, Michael B -- CA042063/CA/NCI NIH HHS/ -- GM60594/GM/NIGMS NIH HHS/ -- GM68762/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2005 Aug 12;309(5737):1074-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E18-580, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16099986" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/*cytology ; Animals ; Bone Morphogenetic Protein 2 ; Bone Morphogenetic Proteins/pharmacology ; Cell Differentiation ; Cell Line ; Core Binding Factor Alpha 1 Subunit ; Gene Expression Regulation, Developmental ; Humans ; Mesenchymal Stromal Cells/*cytology/physiology ; Mice ; Neoplasm Proteins/metabolism ; Oligonucleotides, Antisense ; Osteoblasts/*cytology ; Osteocalcin/genetics ; Osteogenesis ; PPAR gamma/metabolism ; Promoter Regions, Genetic ; Protein Structure, Tertiary ; Proteins/chemistry/genetics/*physiology ; RNA, Small Interfering ; Transcription Factors/chemistry/genetics/metabolism/*physiology ; Transcriptional Activation ; Transfection ; Transforming Growth Factor beta/pharmacology ; Zebrafish ; Zebrafish Proteins/genetics/physiology
    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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  • 8
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    A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-12-13
    Description: Signal transduction pathways control cellular responses to stimuli, but it is unclear how molecular information is processed as a network. We constructed a systems model of 7980 intracellular signaling events that directly links measurements to 1440 response outputs associated with apoptosis. The model accurately predicted multiple time-dependent apoptotic responses induced by a combination of the death-inducing cytokine tumor necrosis factor with the prosurvival factors epidermal growth factor and insulin. By capturing the role of unsuspected autocrine circuits activated by transforming growth factor-alpha and interleukin-1alpha, the model revealed new molecular mechanisms connecting signaling to apoptosis. The model derived two groupings of intracellular signals that constitute fundamental dimensions (molecular "basis axes") within the apoptotic signaling network. Projection along these axes captures the entire measured apoptotic network, suggesting that cell survival is determined by signaling through this canonical basis set.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Janes, Kevin A -- Albeck, John G -- Gaudet, Suzanne -- Sorger, Peter K -- Lauffenburger, Douglas A -- Yaffe, Michael B -- GM059281/GM/NIGMS NIH HHS/ -- P50-GM68762/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2005 Dec 9;310(5754):1646-53.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biological Engineering Division, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16339439" target="_blank"〉PubMed〈/a〉
    Keywords: *Apoptosis ; Autocrine Communication ; Cell Survival ; Cytokines/*physiology ; Epidermal Growth Factor/physiology ; HT29 Cells ; Humans ; Insulin/physiology ; Interleukin-1/physiology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Least-Squares Analysis ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinases/metabolism ; Models, Biological ; *Signal Transduction ; *Systems Biology ; Systems Theory ; Transforming Growth Factor alpha/physiology ; Tumor Necrosis Factor-alpha/*physiology
    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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  • 9
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    BRCT repeats as phosphopeptide-binding modules involved in protein targeting (2003)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2003-10-25
    Description: We used a proteomic approach to identify phosphopeptide-binding modules mediating signal transduction events in the DNA damage response pathway. Using a library of partially degenerate phosphopeptides, we identified tandem BRCT (BRCA1 carboxyl-terminal) domains in PTIP (Pax transactivation domain-interacting protein) and in BRCA1 as phosphoserine- or phosphothreonine-specific binding modules that recognize substrates phosphorylated by the kinases ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia- and RAD3-related) in response to gamma-irradiation. PTIP tandem BRCT domains are responsible for phosphorylation-dependent protein localization into 53BP1- and phospho-H2AX (gamma-H2AX)-containing nuclear foci, a marker of DNA damage. These findings provide a molecular basis for BRCT domain function in the DNA damage response and may help to explain why the BRCA1 BRCT domain mutation Met1775 --〉 Arg, which fails to bind phosphopeptides, predisposes women to breast and ovarian cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Manke, Isaac A -- Lowery, Drew M -- Nguyen, Anhco -- Yaffe, Michael B -- GM60594/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2003 Oct 24;302(5645):636-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/14576432" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Ataxia Telangiectasia Mutated Proteins ; BRCA1 Protein/*chemistry/*metabolism ; Caffeine/pharmacology ; Calorimetry ; Carrier Proteins/*chemistry/*metabolism ; Cell Cycle Proteins/antagonists & inhibitors/metabolism ; Cell Nucleus/metabolism ; Cytosol/metabolism ; DNA Damage ; DNA-Binding Proteins ; Gamma Rays ; Humans ; Nuclear Proteins/*chemistry/*metabolism ; Peptide Library ; Phosphopeptides/*metabolism ; Phosphorylation ; Phosphoserine/metabolism ; Phosphothreonine/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; Proteomics ; Signal Transduction ; Tumor Cells, Cultured ; Tumor Suppressor Proteins
    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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  • 10
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    The bromodomain protein Brd4 insulates chromatin from DNA damage signalling (2013)
    Nature Publishing Group (NPG)
    Details
    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
    Published by Nature Publishing Group (NPG)
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