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  • 1
    Publication Date: 2012-12-22
    Description: Bats are the only mammals capable of sustained flight and are notorious reservoir hosts for some of the world's most highly pathogenic viruses, including Nipah, Hendra, Ebola, and severe acute respiratory syndrome (SARS). To identify genetic changes associated with the development of bat-specific traits, we performed whole-genome sequencing and comparative analyses of two distantly related species, fruit bat Pteropus alecto and insectivorous bat Myotis davidii. We discovered an unexpected concentration of positively selected genes in the DNA damage checkpoint and nuclear factor kappaB pathways that may be related to the origin of flight, as well as expansion and contraction of important gene families. Comparison of bat genomes with other mammalian species has provided new insights into bat biology and evolution.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Guojie -- Cowled, Christopher -- Shi, Zhengli -- Huang, Zhiyong -- Bishop-Lilly, Kimberly A -- Fang, Xiaodong -- Wynne, James W -- Xiong, Zhiqiang -- Baker, Michelle L -- Zhao, Wei -- Tachedjian, Mary -- Zhu, Yabing -- Zhou, Peng -- Jiang, Xuanting -- Ng, Justin -- Yang, Lan -- Wu, Lijun -- Xiao, Jin -- Feng, Yue -- Chen, Yuanxin -- Sun, Xiaoqing -- Zhang, Yong -- Marsh, Glenn A -- Crameri, Gary -- Broder, Christopher C -- Frey, Kenneth G -- Wang, Lin-Fa -- Wang, Jun -- New York, N.Y. -- Science. 2013 Jan 25;339(6118):456-60. doi: 10.1126/science.1230835. Epub 2012 Dec 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉BGI-Shenzhen, Shenzhen, 518083, China. zhanggj@genomics.org.cn〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23258410" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; *Biological Evolution ; Chiroptera/*genetics/immunology/physiology ; DNA Damage/genetics ; DNA Repair/genetics ; Echolocation ; Evolution, Molecular ; *Flight, Animal ; Genetic Speciation ; *Genome ; Hibernation/genetics ; High-Throughput Nucleotide Sequencing ; Immunity, Innate/*genetics ; Male ; Molecular Sequence Data ; Phylogeny ; Reactive Oxygen Species/metabolism ; Selection, Genetic ; *Sequence Analysis, DNA ; Species Specificity
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2018-12-06
    Description: Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer, Published online: 05 December 2018; doi:10.1038/s41467-018-07258-y The molecular mechanism underlying the resistance of AKT inhibitors in breast cancer is still elusive. Here, the authors demonstrate that BRD4/FOXO3a axis upregulates CDK6 promoter activity to promote resistance to AKT inhibition in breast cancer cells and that blocking the action of CDK6 re-sensitizes resistant cancer cells to growth inhibition.
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2011-11-18
    Description: Legumes (Fabaceae or Leguminosae) are unique among cultivated plants for their ability to carry out endosymbiotic nitrogen fixation with rhizobial bacteria, a process that takes place in a specialized structure known as the nodule. Legumes belong to one of the two main groups of eurosids, the Fabidae, which includes most species capable of endosymbiotic nitrogen fixation. Legumes comprise several evolutionary lineages derived from a common ancestor 60 million years ago (Myr ago). Papilionoids are the largest clade, dating nearly to the origin of legumes and containing most cultivated species. Medicago truncatula is a long-established model for the study of legume biology. Here we describe the draft sequence of the M. truncatula euchromatin based on a recently completed BAC assembly supplemented with Illumina shotgun sequence, together capturing approximately 94% of all M. truncatula genes. A whole-genome duplication (WGD) approximately 58 Myr ago had a major role in shaping the M. truncatula genome and thereby contributed to the evolution of endosymbiotic nitrogen fixation. Subsequent to the WGD, the M. truncatula genome experienced higher levels of rearrangement than two other sequenced legumes, Glycine max and Lotus japonicus. M. truncatula is a close relative of alfalfa (Medicago sativa), a widely cultivated crop with limited genomics tools and complex autotetraploid genetics. As such, the M. truncatula genome sequence provides significant opportunities to expand alfalfa's genomic toolbox.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272368/" 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/PMC3272368/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Young, Nevin D -- Debelle, Frederic -- Oldroyd, Giles E D -- Geurts, Rene -- Cannon, Steven B -- Udvardi, Michael K -- Benedito, Vagner A -- Mayer, Klaus F X -- Gouzy, Jerome -- Schoof, Heiko -- Van de Peer, Yves -- Proost, Sebastian -- Cook, Douglas R -- Meyers, Blake C -- Spannagl, Manuel -- Cheung, Foo -- De Mita, Stephane -- Krishnakumar, Vivek -- Gundlach, Heidrun -- Zhou, Shiguo -- Mudge, Joann -- Bharti, Arvind K -- Murray, Jeremy D -- Naoumkina, Marina A -- Rosen, Benjamin -- Silverstein, Kevin A T -- Tang, Haibao -- Rombauts, Stephane -- Zhao, Patrick X -- Zhou, Peng -- Barbe, Valerie -- Bardou, Philippe -- Bechner, Michael -- Bellec, Arnaud -- Berger, Anne -- Berges, Helene -- Bidwell, Shelby -- Bisseling, Ton -- Choisne, Nathalie -- Couloux, Arnaud -- Denny, Roxanne -- Deshpande, Shweta -- Dai, Xinbin -- Doyle, Jeff J -- Dudez, Anne-Marie -- Farmer, Andrew D -- Fouteau, Stephanie -- Franken, Carolien -- Gibelin, Chrystel -- Gish, John -- Goldstein, Steven -- Gonzalez, Alvaro J -- Green, Pamela J -- Hallab, Asis -- Hartog, Marijke -- Hua, Axin -- Humphray, Sean J -- Jeong, Dong-Hoon -- Jing, Yi -- Jocker, Anika -- Kenton, Steve M -- Kim, Dong-Jin -- Klee, Kathrin -- Lai, Hongshing -- Lang, Chunting -- Lin, Shaoping -- Macmil, Simone L -- Magdelenat, Ghislaine -- Matthews, Lucy -- McCorrison, Jamison -- Monaghan, Erin L -- Mun, Jeong-Hwan -- Najar, Fares Z -- Nicholson, Christine -- Noirot, Celine -- O'Bleness, Majesta -- Paule, Charles R -- Poulain, Julie -- Prion, Florent -- Qin, Baifang -- Qu, Chunmei -- Retzel, Ernest F -- Riddle, Claire -- Sallet, Erika -- Samain, Sylvie -- Samson, Nicolas -- Sanders, Iryna -- Saurat, Olivier -- Scarpelli, Claude -- Schiex, Thomas -- Segurens, Beatrice -- Severin, Andrew J -- Sherrier, D Janine -- Shi, Ruihua -- Sims, Sarah -- Singer, Susan R -- Sinharoy, Senjuti -- Sterck, Lieven -- Viollet, Agnes -- Wang, Bing-Bing -- Wang, Keqin -- Wang, Mingyi -- Wang, Xiaohong -- Warfsmann, Jens -- Weissenbach, Jean -- White, Doug D -- White, Jim D -- Wiley, Graham B -- Wincker, Patrick -- Xing, Yanbo -- Yang, Limei -- Yao, Ziyun -- Ying, Fu -- Zhai, Jixian -- Zhou, Liping -- Zuber, Antoine -- Denarie, Jean -- Dixon, Richard A -- May, Gregory D -- Schwartz, David C -- Rogers, Jane -- Quetier, Francis -- Town, Christopher D -- Roe, Bruce A -- BB/G023832/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BBS/B/11524/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2011 Nov 16;480(7378):520-4. doi: 10.1038/nature10625.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant Pathology, University of Minnesota, St Paul, Minnesota 55108, USA. neviny@umn.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22089132" target="_blank"〉PubMed〈/a〉
    Keywords: *Biological Evolution ; *Genome, Plant ; Medicago truncatula/*genetics/*microbiology ; Molecular Sequence Data ; Nitrogen Fixation/genetics ; Rhizobium/*physiology ; Soybeans/genetics ; *Symbiosis ; Synteny ; Vitis/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    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
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  • 5
    Publication Date: 2018-12-15
    Description: Purpose: Identification of novel strategies to expand the use of PARP inhibitors beyond BRCA deficiency is of great interest in personalized medicine. Here, we investigated the unannotated role of Kub5-Hera RPRD1B (K-H) in homologous recombination (HR) repair and its potential clinical significance in targeted cancer therapy. Experimental Design: Functional characterization of K-H alterations on HR repair of double-strand breaks (DSB) were assessed by targeted gene silencing, plasmid reporter assays, immunofluorescence, and Western blots. Cell survival with PARP inhibitors was evaluated through colony-forming assays and statistically analyzed for correlation with K-H expression in various BRCA1/2 nonmutated breast cancers. Gene expression microarray/qPCR analyses, chromatin immunoprecipitation, and rescue experiments were used to investigate molecular mechanisms of action. Results: K-H expression loss correlates with rucaparib LD 50 values in a panel of BRCA1/2 nonmutated breast cancers. Mechanistically, K-H depletion promotes BRCAness , where extensive upregulation of PARP1 activity was required for the survival of breast cancer cells. PARP inhibition in these cells led to synthetic lethality that was rescued by wild-type K-H reexpression, but not by a mutant K-H (p.R106A) that weakly binds RNAPII. K-H mediates HR by facilitating recruitment of RNAPII to the promoter region of a critical DNA damage response and repair effector, cyclin-dependent kinase 1 ( CDK1 ). Conclusions: Cancer cells with low K-H expression may have exploitable BRCAness properties that greatly expand the use of PARP inhibitors beyond BRCA mutations. Our results suggest that aberrant K-H alterations may have vital translational implications in cellular responses/survival to DNA damage, carcinogenesis, and personalized medicine.
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 6
    Publication Date: 2013-11-08
    Description: Acyl carrier protein represents one of the most highly conserved proteins across all domains of life and is nature's way of transporting hydrocarbon chains in vivo. Notably, type II acyl carrier proteins serve as a crucial interaction hub in primary cellular metabolism by communicating transiently between partner enzymes of the numerous biosynthetic pathways. However, the highly transient nature of such interactions and the inherent conformational mobility of acyl carrier protein have stymied previous attempts to visualize structurally acyl carrier protein tied to an overall catalytic cycle. This is essential to understanding a fundamental aspect of cellular metabolism leading to compounds that are not only useful to the cell, but also of therapeutic value. For example, acyl carrier protein is central to the biosynthesis of the lipid A (endotoxin) component of lipopolysaccharides in Gram-negative microorganisms, which is required for their growth and survival, and is an activator of the mammalian host's immune system, thus emerging as an important therapeutic target. During lipid A synthesis (Raetz pathway), acyl carrier protein shuttles acyl intermediates linked to its prosthetic 4'-phosphopantetheine group among four acyltransferases, including LpxD. Here we report the crystal structures of three forms of Escherichia coli acyl carrier protein engaging LpxD, which represent stalled substrate and liberated products along the reaction coordinate. The structures show the intricate interactions at the interface that optimally position acyl carrier protein for acyl delivery and that directly involve the pantetheinyl group. Conformational differences among the stalled acyl carrier proteins provide the molecular basis for the association-dissociation process. An unanticipated conformational shift of 4'-phosphopantetheine groups within the LpxD catalytic chamber shows an unprecedented role of acyl carrier protein in product release.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947097/" 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/PMC3947097/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Masoudi, Ali -- Raetz, Christian R H -- Zhou, Pei -- Pemble, Charles W 4th -- AI-055588/AI/NIAID NIH HHS/ -- GM-51310/GM/NIGMS NIH HHS/ -- P30 CA014236/CA/NCI NIH HHS/ -- R01 AI055588/AI/NIAID NIH HHS/ -- R01 GM051310/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jan 16;505(7483):422-6. doi: 10.1038/nature12679. Epub 2013 Nov 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA. ; 1] Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA [2]. ; 1] Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Duke Macromolecular Crystallography Center, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24196711" target="_blank"〉PubMed〈/a〉
    Keywords: Acyl Carrier Protein/*chemistry/*metabolism ; Acyltransferases/chemistry/metabolism ; *Biocatalysis ; Crystallography, X-Ray ; Escherichia coli/*chemistry ; Hydrolysis ; Lipid A/*biosynthesis/metabolism ; Models, Molecular ; Protein Binding ; Protein Conformation
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2018-08-01
    Description: Nitrogen (N) is a non-mineral macronutrient essential for plant growth and development. Oilseed rape (A n A n C n C n , 2 n = 4 x = 38) has a high requirement for N nutrients whereas showing the lowest N use efficiency (NUE) among crops. The mechanisms underlying NUE regulation in Brassica napus remain unclear because of genome complexity. In this study, we performed high-depth and -coverage whole-genome re-sequencing (WGS) of an N-efficient (higher NUE) genotype "XY15" and an N-inefficient (lower NUE) genotype "814" of rapeseed. More than 687 million 150-bp paired-end reads were generated, which provided about 93% coverage and 50 x depth of the rapeseed genome. Applying stringent parameters, we identified a total of 1,449,157 single-nucleotide polymorphisms (SNPs), 335,228 InDels, 175,602 structure variations (SVs) and 86,280 copy number variations (CNVs) between the N-efficient and -inefficient genotypes. The largest proportion of various DNA polymorphisms occurred in the inter-genic regions. Unlike CNVs, the SNP/InDel and SV polymorphisms showed variation bias of the A n and C n subgenomes, respectively. Gene ontology analysis showed the genetic variants were mapped onto the genes involving N compound transport and ATPase complex metabolism, but not including N assimilation-related genes. On basis of identification of N-starvation responsive genes through high-throughput expression profiling, we also mapped these variants onto some key NUE-regulating genes, and validated their significantly differential expression between the N-efficient and -inefficient genotypes through qRT-PCR assays. Our data provide genome-wide high resolution DNA variants underlying NUE divergence in allotetraploid rapeseed genotypes, which would expedite the effective identification and functional validation of key NUE-regulating genes through genomics-assisted improvement of crop nutrient efficiency.
    Electronic ISSN: 2160-1836
    Topics: Biology
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  • 8
    Publication Date: 2018-04-28
    Description: Apoptosis is an essential strategy of host defense responses and is used by viruses to maintain their life cycles. However, the apoptotic signals involved in virus replication are poorly known. In the present study, we report the molecular mechanism of apoptotic induction by the viral protein ORF4, a newly identified viral protein of porcine circovirus type 2 (PCV2). Apoptosis detection revealed not only that the activity of caspase-3 and -9 is increased in PCV2-infected and ORF4-transfected cells but also that cytochrome c release from the mitochondria to the cytosol is upregulated. Subsequently, ORF4 protein colocalization with adenine nucleotide translocase 3 (ANT3) was observed using structured illumination microscopy. Moreover, coimmunoprecipitation and pulldown analyses confirmed that the ORF4 protein interacts directly with mitochondrial ANT3 (mtANT3). Binding domain analysis further confirmed that N-terminal residues 1 to 30 of the ORF4 protein, comprising a mitochondrial targeting signal, are essential for the interaction with ANT3. Knockdown of ANT3 markedly inhibited the apoptotic induction of both ORF4 protein and PCV2, indicating that ANT3 plays an important role in ORF4 protein-induced apoptosis during PCV2 infection. Taken together, these data indicate that the ORF4 protein is a mitochondrial targeting protein that induces apoptosis by interacting with ANT3 through the mitochondrial pathway. IMPORTANCE The porcine circovirus type 2 (PCV2) protein ORF4 is a newly identified viral protein; however, little is known about its functions. Apoptosis is an essential strategy of the host defense response and is used by viruses to maintain their life cycles. In the present study, we report the molecular mechanism of the apoptosis induced by the ORF4 protein. The ORF4 protein contains a mitochondrial targeting signal and is an unstable protein that is degraded by the proteasome-dependent pathway. Viral protein ORF4 triggers caspase-3- and -9-dependent cellular apoptosis in mitochondria by directly binding to ANT3. We conclude that the ORF4 protein is a mitochondrial targeting protein and reveal a mechanism whereby circovirus recruits ANT3 to induce apoptosis.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 9
  • 10
    Publication Date: 2018-04-03
    Description: Obesity is associated with an increased incidence of high-grade prostate cancer and poor prognosis for prostate cancer patients. Recently, we showed that obesity-related periprostatic white adipose tissue (WAT) inflammation, characterized by crown-like structures (CLS) consisting of dead or dying adipocytes surrounded by macrophages, was associated with high-grade prostate cancer. It is possible, therefore, that agents that suppress periprostatic WAT inflammation will alter the development or progression of prostate cancer. Pioglitazone, a ligand of PPAR, is used to treat diabetes and possesses anti-inflammatory properties. Here, our main objectives were to determine whether pioglitazone inhibited obesity-related periprostatic WAT inflammation in mice and then to elucidate the underlying mechanism. Treatment with pioglitazone reduced the density of CLS in periprostatic fat and suppressed levels of TNFα, TGFβ, and the chemokine monocyte chemoattractant protein-1 (MCP-1). Importantly, the ability of pioglitazone to suppress periprostatic WAT inflammation was abrogated in MCP-1 knockout mice. Pioglitazone caused dose-dependent induction of both adiponectin, an anti-inflammatory adipokine, and its receptor AdipoR2 in cultured 3T3-L1 cells and in periprostatic WAT of obese mice. Pioglitazone blocked TNFα-mediated induction of MCP-1 in 3T3-L1 cells, an effect that was attenuated when either adiponectin or AdipoR2 were silenced. Taken together, pioglitazone-mediated induction of adiponectin suppressed the elevation in MCP-1 levels, thereby attenuating obesity-related periprostatic WAT inflammation. These findings strengthen the rationale for future efforts to determine whether targeting the PPAR–adiponectin–MCP-1 axis will decrease periprostatic adipose inflammation and thereby reduce the risk of high-grade prostate cancer or improve outcomes for men with prostate cancer. Cancer Prev Res; 11(4); 215–26. ©2017 AACR .
    Print ISSN: 1940-6207
    Electronic ISSN: 1940-6215
    Topics: Medicine
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