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  • 1
    Publication Date: 2011-06-10
    Description: Cyclin D1 is a component of the core cell cycle machinery. Abnormally high levels of cyclin D1 are detected in many human cancer types. To elucidate the molecular functions of cyclin D1 in human cancers, we performed a proteomic screen for cyclin D1 protein partners in several types of human tumours. Analyses of cyclin D1 interactors revealed a network of DNA repair proteins, including RAD51, a recombinase that drives the homologous recombination process. We found that cyclin D1 directly binds RAD51, and that cyclin D1-RAD51 interaction is induced by radiation. Like RAD51, cyclin D1 is recruited to DNA damage sites in a BRCA2-dependent fashion. Reduction of cyclin D1 levels in human cancer cells impaired recruitment of RAD51 to damaged DNA, impeded the homologous recombination-mediated DNA repair, and increased sensitivity of cells to radiation in vitro and in vivo. This effect was seen in cancer cells lacking the retinoblastoma protein, which do not require D-cyclins for proliferation. These findings reveal an unexpected function of a core cell cycle protein in DNA repair and suggest that targeting cyclin D1 may be beneficial also in retinoblastoma-negative cancers which are currently thought to be unaffected by cyclin D1 inhibition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134411/" 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/PMC3134411/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jirawatnotai, Siwanon -- Hu, Yiduo -- Michowski, Wojciech -- Elias, Joshua E -- Becks, Lisa -- Bienvenu, Frederic -- Zagozdzon, Agnieszka -- Goswami, Tapasree -- Wang, Yaoyu E -- Clark, Alan B -- Kunkel, Thomas A -- van Harn, Tanja -- Xia, Bing -- Correll, Mick -- Quackenbush, John -- Livingston, David M -- Gygi, Steven P -- Sicinski, Piotr -- P01 CA080111/CA/NCI NIH HHS/ -- P01 CA080111-12/CA/NCI NIH HHS/ -- P01 CA109901/CA/NCI NIH HHS/ -- P01 CA109901-07/CA/NCI NIH HHS/ -- P30 AI060354/AI/NIAID NIH HHS/ -- R01 CA083688/CA/NCI NIH HHS/ -- R01 CA083688-10/CA/NCI NIH HHS/ -- R01 CA138804/CA/NCI NIH HHS/ -- R01 CA138804-02/CA/NCI NIH HHS/ -- Z01 ES065089-11/Intramural NIH HHS/ -- England -- Nature. 2011 Jun 8;474(7350):230-4. doi: 10.1038/nature10155.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21654808" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Comet Assay ; Cyclin D1/deficiency/*metabolism ; DNA Damage/radiation effects ; *DNA Repair/radiation effects ; HeLa Cells ; Humans ; Mice ; Neoplasms/genetics/*metabolism/pathology ; Protein Binding/radiation effects ; *Protein Interaction Mapping ; Rad51 Recombinase/*metabolism ; Radiation, Ionizing ; Recombination, Genetic/genetics ; Retinoblastoma Protein/deficiency
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  • 2
    Publication Date: 2012-01-13
    Description: Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-gamma co-activator-1 alpha (PGC1-alpha). Here we show in mouse that PGC1-alpha expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3522098/" 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/PMC3522098/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bostrom, Pontus -- Wu, Jun -- Jedrychowski, Mark P -- Korde, Anisha -- Ye, Li -- Lo, James C -- Rasbach, Kyle A -- Bostrom, Elisabeth Almer -- Choi, Jang Hyun -- Long, Jonathan Z -- Kajimura, Shingo -- Zingaretti, Maria Cristina -- Vind, Birgitte F -- Tu, Hua -- Cinti, Saverio -- Hojlund, Kurt -- Gygi, Steven P -- Spiegelman, Bruce M -- DK31405/DK/NIDDK NIH HHS/ -- DK54477/DK/NIDDK NIH HHS/ -- K99 DK087853/DK/NIDDK NIH HHS/ -- R01 DK054477/DK/NIDDK NIH HHS/ -- R01 DK061562/DK/NIDDK NIH HHS/ -- R37 DK031405/DK/NIDDK NIH HHS/ -- England -- Nature. 2012 Jan 11;481(7382):463-8. doi: 10.1038/nature10777.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22237023" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/cytology/drug effects/metabolism ; Adipose Tissue, Brown/*cytology/drug effects/metabolism ; Adipose Tissue, White/*cytology/drug effects/metabolism ; Animals ; Cell Respiration/drug effects ; Cells, Cultured ; Culture Media, Conditioned/pharmacology ; Energy Metabolism/drug effects/genetics/physiology ; Exercise/physiology ; Gene Expression Regulation/drug effects/genetics ; Hormones/metabolism/secretion ; Humans ; Insulin Resistance/physiology ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Ion Channels/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; Mitochondrial Proteins/metabolism ; Models, Animal ; Muscle Cells/metabolism ; Obesity/blood/chemically induced/prevention & control ; Physical Conditioning, Animal/physiology ; Plasma/chemistry ; Subcutaneous Fat/cytology/drug effects/metabolism ; *Thermogenesis/drug effects/genetics ; Trans-Activators/deficiency/genetics/*metabolism/secretion ; Transcription Factors
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2016-03-31
    Description: Brown and beige adipose tissues can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1). Thermogenesis from these adipocytes can combat obesity and diabetes, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Here we show that acutely activated thermogenesis in brown adipose tissue is defined by a substantial increase in levels of mitochondrial reactive oxygen species (ROS). Remarkably, this process supports in vivo thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole-body energy expenditure. We further establish that thermogenic ROS alter the redox status of cysteine thiols in brown adipose tissue to drive increased respiration, and that Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine-nucleotide-inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify mitochondrial ROS induction in brown adipose tissue as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chouchani, Edward T -- Kazak, Lawrence -- Jedrychowski, Mark P -- Lu, Gina Z -- Erickson, Brian K -- Szpyt, John -- Pierce, Kerry A -- Laznik-Bogoslavski, Dina -- Vetrivelan, Ramalingam -- Clish, Clary B -- Robinson, Alan J -- Gygi, Steve P -- Spiegelman, Bruce M -- DK31405/DK/NIDDK NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2016 Apr 7;532(7597):112-6. doi: 10.1038/nature17399. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. ; Department of Neurology, Harvard Medical School, Boston, Massachusetts 02215, USA. ; MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027295" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/chemistry/cytology/metabolism ; Animals ; Cell Respiration ; Cysteine/*chemistry/genetics/metabolism ; *Energy Metabolism/drug effects ; Female ; Humans ; Ion Channels/*chemistry/deficiency/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects/*metabolism ; Mitochondrial Proteins/*chemistry/deficiency/genetics/*metabolism ; Mutant Proteins/chemistry/genetics/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; Sulfhydryl Compounds/metabolism ; *Thermogenesis/drug effects
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  • 4
    Publication Date: 2008-11-11
    Description: Repetitive DNA sequences, which constitute half the genome in some organisms, often undergo homologous recombination. This can instigate genomic instability resulting from a gain or loss of DNA. Assembly of DNA into silent chromatin is generally thought to serve as a mechanism ensuring repeat stability by limiting access to the recombination machinery. Consistent with this notion is the observation, in the budding yeast Saccharomyces cerevisiae, that stability of the highly repetitive ribosomal DNA (rDNA) sequences requires a Sir2-containing chromatin silencing complex that also inhibits transcription from foreign promoters and transposons inserted within the repeats by a process called rDNA silencing. Here we describe a protein network that stabilizes rDNA repeats of budding yeast by means of interactions between rDNA-associated silencing proteins and two proteins of the inner nuclear membrane (INM). Deletion of either the INM or silencing proteins reduces perinuclear rDNA positioning, disrupts the nucleolus-nucleoplasm boundary, induces the formation of recombination foci, and destabilizes the repeats. In addition, artificial targeting of rDNA repeats to the INM suppresses the instability observed in cells lacking an rDNA-associated silencing protein that is typically required for peripheral tethering of the repeats. Moreover, in contrast to Sir2 and its associated nucleolar factors, the INM proteins are not required for rDNA silencing, indicating that Sir2-dependent silencing is not sufficient to inhibit recombination within the rDNA locus. These findings demonstrate a role for INM proteins in the perinuclear localization of chromosomes and show that tethering to the nuclear periphery is required for the stability of rDNA repeats. The INM proteins studied here are conserved and have been implicated in chromosome organization in metazoans. Our results therefore reveal an ancient mechanism in which interactions between INM proteins and chromosomal proteins ensure genome stability.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596277/" 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/PMC2596277/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mekhail, Karim -- Seebacher, Jan -- Gygi, Steven P -- Moazed, Danesh -- R01 GM079535/GM/NIGMS NIH HHS/ -- R01 GM079535-02/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Dec 4;456(7222):667-70. doi: 10.1038/nature07460. Epub 2008 Nov 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18997772" target="_blank"〉PubMed〈/a〉
    Keywords: Chromosomal Position Effects ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosome Positioning ; Chromosomes, Fungal/genetics/*metabolism ; DNA, Ribosomal/*genetics/metabolism ; Gene Expression Regulation, Fungal ; *Gene Silencing ; Genomic Instability/*genetics ; Nuclear Envelope/chemistry/genetics/*metabolism ; Protein Binding ; Recombination, Genetic/genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Saccharomyces cerevisiae/*cytology/*genetics
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  • 5
    Publication Date: 2009-05-05
    Description: The proteasome is a protease that controls diverse processes in eukaryotic cells. Its regulatory particle (RP) initiates the degradation of ubiquitin-protein conjugates by unfolding the substrate and translocating it into the proteasome core particle (CP) to be degraded. The RP has 19 subunits, and their pathway of assembly is not understood. Here we show that in the yeast Saccharomyces cerevisiae three proteins are found associated with RP but not with the RP-CP holoenzyme: Nas6, Rpn14 and Hsm3. Mutations in the corresponding genes confer proteasome loss-of-function phenotypes, despite their virtual absence from the holoenzyme. These effects result from deficient RP assembly. Thus, Nas6, Rpn14 and Hsm3 are RP chaperones. The RP contains six ATPases-the Rpt proteins-and each RP chaperone binds to the carboxy-terminal domain of a specific Rpt. We show in an accompanying study that RP assembly is templated through the Rpt C termini, apparently by their insertion into binding pockets in the CP. Thus, RP chaperones may regulate proteasome assembly by directly restricting the accessibility of Rpt C termini to the CP. In addition, competition between the RP chaperones and the CP for Rpt engagement may explain the release of RP chaperones as proteasomes mature.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727592/" 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/PMC2727592/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roelofs, Jeroen -- Park, Soyeon -- Haas, Wilhelm -- Tian, Geng -- McAllister, Fiona E -- Huo, Ying -- Lee, Byung-Hoon -- Zhang, Fan -- Shi, Yigong -- Gygi, Steven P -- Finley, Daniel -- 5F32GM75737-2/GM/NIGMS NIH HHS/ -- GM043601/GM/NIGMS NIH HHS/ -- GM67945/GM/NIGMS NIH HHS/ -- R37 GM043601/GM/NIGMS NIH HHS/ -- R37 GM043601-19/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Jun 11;459(7248):861-5. doi: 10.1038/nature08063.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19412159" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/metabolism ; Carrier Proteins/genetics/metabolism ; Conserved Sequence ; Evolution, Molecular ; Holoenzymes/chemistry/metabolism ; Humans ; Models, Molecular ; Molecular Chaperones/genetics/*metabolism ; Mutation ; Phenotype ; Proteasome Endopeptidase Complex/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Proto-Oncogene Proteins/genetics/metabolism ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/genetics/metabolism
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  • 6
    Publication Date: 2009-05-05
    Description: Substrates of the proteasome are recognized and unfolded by the regulatory particle, and then translocated into the core particle (CP) to be degraded. A hetero-hexameric ATPase ring, containing subunits Rpt1-6, is situated within the base subassembly of the regulatory particle. The ATPase ring sits atop the CP, with the Rpt carboxy termini inserted into pockets in the CP. Here we identify a previously unknown function of the Rpt proteins in proteasome biogenesis through deleting the C-terminal residue from each Rpt in the yeast Saccharomyces cerevisiae. Our results indicate that assembly of the hexameric ATPase ring is templated on the CP. We have also identified an apparent intermediate in base assembly, BP1, which contains Rpn1, three Rpts and Hsm3, a chaperone for base assembly. The Rpt proteins with the strongest assembly phenotypes, Rpt4 and Rpt6, were absent from BP1. We propose that Rpt4 and Rpt6 form a nucleating complex to initiate base assembly, and that this complex is subsequently joined by BP1 to complete the Rpt ring. Our studies show that assembly of the proteasome base is a rapid yet highly orchestrated process.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722381/" 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/PMC2722381/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Soyeon -- Roelofs, Jeroen -- Kim, Woong -- Robert, Jessica -- Schmidt, Marion -- Gygi, Steven P -- Finley, Daniel -- 5F32GM75737-2/GM/NIGMS NIH HHS/ -- F32 GM075737-01A2/GM/NIGMS NIH HHS/ -- GM043601/GM/NIGMS NIH HHS/ -- GM67945/GM/NIGMS NIH HHS/ -- R01 GM084228/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Jun 11;459(7248):866-70. doi: 10.1038/nature08065.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19412160" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/*chemistry/genetics/*metabolism ; Molecular Chaperones/metabolism ; Proteasome Endopeptidase Complex/*biosynthesis/*chemistry/genetics/metabolism ; Saccharomyces cerevisiae/*enzymology/genetics ; Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism
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  • 7
    Publication Date: 2010-09-11
    Description: Proteasomes, the primary mediators of ubiquitin-protein conjugate degradation, are regulated through complex and poorly understood mechanisms. Here we show that USP14, a proteasome-associated deubiquitinating enzyme, can inhibit the degradation of ubiquitin-protein conjugates both in vitro and in cells. A catalytically inactive variant of USP14 has reduced inhibitory activity, indicating that inhibition is mediated by trimming of the ubiquitin chain on the substrate. A high-throughput screen identified a selective small-molecule inhibitor of the deubiquitinating activity of human USP14. Treatment of cultured cells with this compound enhanced degradation of several proteasome substrates that have been implicated in neurodegenerative disease. USP14 inhibition accelerated the degradation of oxidized proteins and enhanced resistance to oxidative stress. Enhancement of proteasome activity through inhibition of USP14 may offer a strategy to reduce the levels of aberrant proteins in cells under proteotoxic stress.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939003/" 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/PMC2939003/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Byung-Hoon -- Lee, Min Jae -- Park, Soyeon -- Oh, Dong-Chan -- Elsasser, Suzanne -- Chen, Ping-Chung -- Gartner, Carlos -- Dimova, Nevena -- Hanna, John -- Gygi, Steven P -- Wilson, Scott M -- King, Randall W -- Finley, Daniel -- DK082906/DK/NIDDK NIH HHS/ -- GM65592/GM/NIGMS NIH HHS/ -- GM66492/GM/NIGMS NIH HHS/ -- NS047533/NS/NINDS NIH HHS/ -- P30 NS057098/NS/NINDS NIH HHS/ -- P30 NS057098-049002/NS/NINDS NIH HHS/ -- R01 GM066492/GM/NIGMS NIH HHS/ -- R01 GM067945/GM/NIGMS NIH HHS/ -- R01 NS047533/NS/NINDS NIH HHS/ -- R01 NS047533-06A2/NS/NINDS NIH HHS/ -- England -- Nature. 2010 Sep 9;467(7312):179-84. doi: 10.1038/nature09299.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20829789" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cells, Cultured ; Humans ; Mice ; Proteasome Endopeptidase Complex/*metabolism ; Proteins/*metabolism ; Ubiquitin Thiolesterase/*antagonists & inhibitors ; Ubiquitination
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  • 8
    Publication Date: 2010-06-22
    Description: Autophagy, the process by which proteins and organelles are sequestered in autophagosomal vesicles and delivered to the lysosome/vacuole for degradation, provides a primary route for turnover of stable and defective cellular proteins. Defects in this system are linked with numerous human diseases. Although conserved protein kinase, lipid kinase and ubiquitin-like protein conjugation subnetworks controlling autophagosome formation and cargo recruitment have been defined, our understanding of the global organization of this system is limited. Here we report a proteomic analysis of the autophagy interaction network in human cells under conditions of ongoing (basal) autophagy, revealing a network of 751 interactions among 409 candidate interacting proteins with extensive connectivity among subnetworks. Many new autophagy interaction network components have roles in vesicle trafficking, protein or lipid phosphorylation and protein ubiquitination, and affect autophagosome number or flux when depleted by RNA interference. The six ATG8 orthologues in humans (MAP1LC3/GABARAP proteins) interact with a cohort of 67 proteins, with extensive binding partner overlap between family members, and frequent involvement of a conserved surface on ATG8 proteins known to interact with LC3-interacting regions in partner proteins. These studies provide a global view of the mammalian autophagy interaction landscape and a resource for mechanistic analysis of this critical protein homeostasis pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901998/" 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/PMC2901998/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Behrends, Christian -- Sowa, Mathew E -- Gygi, Steven P -- Harper, J Wade -- R01 AG011085/AG/NIA NIH HHS/ -- R01 AG011085-18/AG/NIA NIH HHS/ -- R01 GM054137/GM/NIGMS NIH HHS/ -- R01 GM054137-14/GM/NIGMS NIH HHS/ -- R01 GM054137-14S1/GM/NIGMS NIH HHS/ -- R01 GM054137-15/GM/NIGMS NIH HHS/ -- R01 GM070565/GM/NIGMS NIH HHS/ -- R01 GM070565-05S1/GM/NIGMS NIH HHS/ -- R01 GM095567/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Jul 1;466(7302):68-76. doi: 10.1038/nature09204. Epub 2010 Jun 20.〈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/20562859" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics/metabolism ; Autophagy/genetics/*physiology ; Homeostasis ; Humans ; Microfilament Proteins/genetics/metabolism ; Phagosomes ; Phosphorylation ; Protein Binding ; *Protein Interaction Mapping ; Proteomics ; RNA Interference ; Reproducibility of Results ; Ubiquitination
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  • 9
    Publication Date: 2013-03-19
    Description: The PARKIN ubiquitin ligase (also known as PARK2) and its regulatory kinase PINK1 (also known as PARK6), often mutated in familial early-onset Parkinson's disease, have central roles in mitochondrial homeostasis and mitophagy. Whereas PARKIN is recruited to the mitochondrial outer membrane (MOM) upon depolarization via PINK1 action and can ubiquitylate porin, mitofusin and Miro proteins on the MOM, the full repertoire of PARKIN substrates--the PARKIN-dependent ubiquitylome--remains poorly defined. Here we use quantitative diGly capture proteomics (diGly) to elucidate the ubiquitylation site specificity and topology of PARKIN-dependent target modification in response to mitochondrial depolarization. Hundreds of dynamically regulated ubiquitylation sites in dozens of proteins were identified, with strong enrichment for MOM proteins, indicating that PARKIN dramatically alters the ubiquitylation status of the mitochondrial proteome. Using complementary interaction proteomics, we found depolarization-dependent PARKIN association with numerous MOM targets, autophagy receptors, and the proteasome. Mutation of the PARKIN active site residue C431, which has been found mutated in Parkinson's disease patients, largely disrupts these associations. Structural and topological analysis revealed extensive conservation of PARKIN-dependent ubiquitylation sites on cytoplasmic domains in vertebrate and Drosophila melanogaster MOM proteins. These studies provide a resource for understanding how the PINK1-PARKIN pathway re-sculpts the proteome to support mitochondrial homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641819/" 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/PMC3641819/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sarraf, Shireen A -- Raman, Malavika -- Guarani-Pereira, Virginia -- Sowa, Mathew E -- Huttlin, Edward L -- Gygi, Steven P -- Harper, J Wade -- CA139885/CA/NCI NIH HHS/ -- GM067945/GM/NIGMS NIH HHS/ -- GM070565/GM/NIGMS NIH HHS/ -- GM095567/GM/NIGMS NIH HHS/ -- R01 GM067945/GM/NIGMS NIH HHS/ -- R01 GM070565/GM/NIGMS NIH HHS/ -- R01 GM095567/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Apr 18;496(7445):372-6. doi: 10.1038/nature12043. Epub 2013 Mar 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23503661" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Drosophila Proteins/metabolism ; Drosophila melanogaster/metabolism ; Humans ; *Membrane Potential, Mitochondrial ; Mice ; Mitochondria/chemistry/*metabolism ; Mitochondrial Membranes/*metabolism ; Mitochondrial Proteins/*metabolism ; Protein Kinases/metabolism ; Proteome/*metabolism ; Proteomics ; Ubiquitin-Protein Ligases/*metabolism ; *Ubiquitination
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2013-10-12
    Description: The Hippo pathway controls metazoan organ growth by regulating cell proliferation and apoptosis. Many components have been identified, but our knowledge of the composition and structure of this pathway is still incomplete. Using existing pathway components as baits, we generated by mass spectrometry a high-confidence Drosophila Hippo protein-protein interaction network (Hippo-PPIN) consisting of 153 proteins and 204 interactions. Depletion of 67% of the proteins by RNA interference regulated the transcriptional coactivator Yorkie (Yki) either positively or negatively. We selected for further characterization a new member of the alpha-arrestin family, Leash, and show that it promotes degradation of Yki through the lysosomal pathway. Given the importance of the Hippo pathway in tumor development, the Hippo-PPIN will contribute to our understanding of this network in both normal growth and cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951131/" 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/PMC3951131/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kwon, Young -- Vinayagam, Arunachalam -- Sun, Xiaoyun -- Dephoure, Noah -- Gygi, Steven P -- Hong, Pengyu -- Perrimon, Norbert -- P01 CA120964/CA/NCI NIH HHS/ -- P01-CA120964/CA/NCI NIH HHS/ -- R01 DK088718/DK/NIDDK NIH HHS/ -- R01-DK088718/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Nov 8;342(6159):737-40. doi: 10.1126/science.1243971. Epub 2013 Oct 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24114784" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Drosophila Proteins/antagonists & inhibitors/genetics/*metabolism ; Drosophila melanogaster/genetics/*metabolism ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; Nuclear Proteins/antagonists & inhibitors/metabolism ; *Protein Interaction Maps ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; Proteome/genetics/metabolism ; RNA Interference ; Trans-Activators/antagonists & inhibitors/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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