15 results on '"Xiaoyou Liang"'
Search Results
2. DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance
- Author
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Martin Schröder, Martin Renatus, Xiaoyou Liang, Fabian Meili, Thomas Zoller, Sandrine Ferrand, Francois Gauter, Xiaoyan Li, Frederic Sigoillot, Scott Gleim, Therese-Marie Stachyra, Jason R. Thomas, Damien Begue, Maryam Khoshouei, Peggy Lefeuvre, Rita Andraos-Rey, BoYee Chung, Renate Ma, Benika Pinch, Andreas Hofmann, Markus Schirle, Niko Schmiedeberg, Patricia Imbach, Delphine Gorses, Keith Calkins, Beatrice Bauer-Probst, Magdalena Maschlej, Matt Niederst, Rob Maher, Martin Henault, John Alford, Erik Ahrne, Luca Tordella, Greg Hollingworth, Nicolas H. Thomä, Anna Vulpetti, Thomas Radimerski, Philipp Holzer, Seth Carbonneau, and Claudio R. Thoma
- Subjects
Science - Abstract
Abstract Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.
- Published
- 2024
- Full Text
- View/download PDF
3. Reinstating targeted protein degradation with DCAF1 PROTACs in CRBN PROTAC resistant settings
- Author
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Martin Schröder, Martin Renatus, Xiaoyou Liang, Fabian Meili, Thomas Zoller, Sandrine Ferrand, Francois Gauter, Xiaoyan Li, Fred Sigoillot, Scott Gleim, Marie-Therese Stachyra, Jason Thomas, Damien Begue, Peggy Lefeuvre, Rita Andraos-Rey, BoYee Chung, Renate Ma, Seth Carbonneau, Benika Pinch, Andreas Hofmann, Markus Schirle, Niko Schmiedberg, Patricia Imbach, Delphine Gorses, Keith Calkins, Bea Bauer-Probst, Magdalena Maschlej, Matt Niederst, Rob Maher, Martin Henault, John Alford, Erik Ahrne, Greg Hollingworth, Nicolas H. Thomä, Anna Vulpetti, Thomas Radimerski, Philipp Holzer, and Claudio R. Thoma
- Abstract
Targeted protein degradation (TPD) of neo-substrates with proteolysis targeting chimeras (PROTACs) or molecular glues has emerged as a key modality in exploring new biology as well as designing new drug candidates where catalytic inhibition is neither efficacious nor an option. TPD is mediated through harnessing E3 ligases and redirecting them to ubiquitinatede novotarget proteins for subsequent proteasomal degradation. Until recently, E3 ligase chemical matter available for mediating TPD has been limited to a relatively low number of ligases, considering that over 600 E3 ligases are encoded by the human genome. In addition, the most utilized ligase for TPD approaches, CRBN, has been observed to be downregulated in settings of acquired resistance to immunomodulatory inhibitory drugs (IMiDs). IMiDs are molecular glues that target IKZF transcription factors to CRBN for degradation. Resistance is potentially accelerated by non-essentiality of CRBN for cell viability. Here we investigated if the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a potent, non-covalent DCAF1 binder. We show that this binder, selective for the CRL4DCAF1E3 ligase complex, can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments confirm specific degradation via the CRL4DCAF1E3 ligase. We further highlight the versatility of DCAF1 for TPD by developing a DCAF1-dasatininb PROTAC targeting multiple cytosolic and membrane bound tyrosine kinases. We expand these findings towards Bruton’s tyrosine kinase (BTK) selective PROTACs and through extensive optimization and characterization efforts share key observations that led to a potent and selective DCAF1-BTK PROTAC (DBt-10). Finally, with this PROTAC DBt-10, we show rescue of BTK degradation in a BTK-dependent, CRBN-degradation-resistant cell line and provide a rationale for E3 ligase swap to overcome CRBN mediated resistance.
- Published
- 2023
- Full Text
- View/download PDF
4. Manumycin Polyketides Act as Molecular Glues Between UBR7 and P53
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Scott M. Brittain, Xiaoyou Liang, Mikiko Okumura, Lynn M. McGregor, Yosuke Isobe, Daniel K. Nomura, Thomas J. Maimone, Ross White, Markus Schirle, William C. Forrester, John A. Tallarico, Michael D. Jones, and Jeffrey Mckenna
- Subjects
natural products ,Molecular Conformation ,chemistry.chemical_compound ,molecular glues ,Drug Discovery ,0303 health sciences ,Tumor ,biology ,Molecular Structure ,Chemistry ,030302 biochemistry & molecular biology ,Limiting ,Small molecule ,Ubiquitin ligase ,Gene Expression Regulation, Neoplastic ,Cross-Linking Reagents ,Gene Knockdown Techniques ,Female ,Biochemistry & Molecular Biology ,Polyunsaturated Alkamides ,Ubiquitin-Protein Ligases ,Static Electricity ,Breast Neoplasms ,Antineoplastic Agents ,covalent ligands ,Computational biology ,Polyenes ,manumycin ,Article ,Cell Line ,03 medical and health sciences ,Structure-Activity Relationship ,Medicinal and Biomolecular Chemistry ,E3 ligases ,Cell Line, Tumor ,Humans ,Chemoproteomics ,asukamycin ,Molecular Biology ,protein-protein interaction (PPI) ,undruggable ,030304 developmental biology ,activity-based protein profiling ,Neoplastic ,Natural product ,Cell Biology ,Anticancer mechanism ,chemoproteomics ,Gene Expression Regulation ,Polyketides ,biology.protein ,Breast cancer cells ,Biochemistry and Cell Biology ,Tumor Suppressor Protein p53 - Abstract
Molecular glues are an intriguing therapeutic modality that harness small-molecules to induce interactions between proteins that typically do not interact. However, such molecules are rare and have been discovered fortuitously, thus limiting their potential as a general strategy for therapeutic intervention. We postulated that natural products bearing one or more electrophilic sites may be an unexplored source of new molecular glues, potentially acting through multi-covalent attachment. Using chemoproteomic platforms, we show that members of the manumycin family of polyketides, which bear multiple potentially reactive sites, target C374 of the putative E3 ligase UBR7 in breast cancer cells and engage in molecular glue interactions with the neo-substrate tumor-suppressor TP53, leading to p53 transcriptional activation and cell death. Our results reveal a novel anti-cancer mechanism of this natural product family and highlight the potential for combining chemoproteomics and multi-covalent natural products for the discovery of new molecular glues.
- Published
- 2020
5. Identification of the HECT E3 ligase UBR5 as a regulator of MYC degradation using a CRISPR/Cas9 screen
- Author
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Britta Knapp, Xiaoyou Liang, Beatrice Bauer-Probst, John S. Reece-Hoyes, Ines Barbosa, Angelica Mendiola, Tamara Zimmermann, Markus Reschke, Lina Schukur, Grainne Kerr, Claudio R. Thoma, Thomas Radimerski, Ole Niewoehner, Scott Gleim, Giorgio G. Galli, and Melivoia Rapti
- Subjects
Cell biology ,Ubiquitin-Protein Ligases ,Regulator ,lcsh:Medicine ,Apoptosis ,medicine.disease_cause ,Article ,Proto-Oncogene Proteins c-myc ,Neoplasms ,medicine ,Tumor Cells, Cultured ,Humans ,lcsh:Science ,Transcription factor ,Cancer ,chemistry.chemical_classification ,DNA ligase ,Multidisciplinary ,biology ,Cell growth ,lcsh:R ,Biological techniques ,Ubiquitination ,Ubiquitin ligase ,chemistry ,Oncology ,Cancer cell ,Proteolysis ,biology.protein ,lcsh:Q ,CRISPR-Cas Systems ,Carcinogenesis ,Genetic screen ,Protein Binding - Abstract
MYC oncoprotein is a multifunctional transcription factor that regulates the expression of a large number of genes involved in cellular growth, proliferation and metabolism. Altered MYC protein level lead to cellular transformation and tumorigenesis. MYC is deregulated in > 50% of human cancers, rendering it an attractive drug target. However, direct inhibition of this class of proteins using conventional small molecules is challenging due to their intrinsically disordered state. To discover novel posttranslational regulators of MYC protein stability and turnover, we established a genetic screen in mammalian cells by combining a fluorescent protein-based MYC abundance sensor, CRISPR/Cas9-based gene knockouts and next-generation sequencing. Our screen identifies UBR5, an E3 ligase of the HECT-type family, as a novel regulator of MYC degradation. Even in the presence of the well-described and functional MYC ligase, FBXW7, UBR5 depletion leads to accumulation of MYC in cells. We demonstrate interaction of UBR5 with MYC and reduced K48-linked ubiquitination of MYC upon loss of UBR5 in cells. Interestingly, in cancer cell lines with amplified MYC expression, depletion of UBR5 resulted in reduced cell survival, as a consequence of MYC stabilization. Finally, we show that MYC and UBR5 are co-amplified in more than 40% of cancer cells and that MYC copy number amplification correlates with enhanced transcriptional output of UBR5. This suggests that UBR5 acts as a buffer in MYC amplified settings and protects these cells from apoptosis.
- Published
- 2020
6. Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C
- Author
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William C. Forrester, Alexia T. Kedves, Quang-Dé Nguyen, Dennis M. Bonal, Sneha Sanghavi, Prafulla C. Gokhale, Elizabeth George, Fred Harbinski, Robert J. Distel, Paul Kirschmeier, Scott Gleim, Michael S. Goldberg, Christina Benander, Xiaoyou Liang, Jeremy L. Jenkins, and Frederic Sigoillot
- Subjects
0301 basic medicine ,education.field_of_study ,biology ,Ubiquitin B ,Population ,General Medicine ,medicine.disease ,Small hairpin RNA ,03 medical and health sciences ,Ovarian tumor ,030104 developmental biology ,Ubiquitin ,biology.protein ,Cancer research ,medicine ,Gene silencing ,Ubiquitin C ,Ovarian cancer ,education - Abstract
Transcriptional repression of ubiquitin B (UBB) is a cancer-subtype-specific alteration that occurs in a substantial population of patients with cancers of the female reproductive tract. UBB is 1 of 2 genes encoding for ubiquitin as a polyprotein consisting of multiple copies of ubiquitin monomers. Silencing of UBB reduces cellular UBB levels and results in an exquisite dependence on ubiquitin C (UBC), the second polyubiquitin gene. UBB is repressed in approximately 30% of high-grade serous ovarian cancer (HGSOC) patients and is a recurrent lesion in uterine carcinosarcoma and endometrial carcinoma. We identified ovarian tumor cell lines that retain UBB in a repressed state, used these cell lines to establish orthotopic ovarian tumors, and found that inducible expression of a UBC-targeting shRNA led to tumor regression, and substantial long-term survival benefit. Thus, we describe a recurrent cancer-specific lesion at the level of ubiquitin production. Moreover, these observations reveal the prognostic value of UBB repression and establish UBC as a promising therapeutic target for ovarian cancer patients with recurrent UBB silencing.
- Published
- 2017
- Full Text
- View/download PDF
7. Identification of a Genomic Island Present in the Majority of Pathogenic Isolates of Pseudomonas aeruginosa
- Author
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Stephen Lory, Xuan-Quynh T. Pham, Maynard V. Olson, and Xiaoyou Liang
- Subjects
Genetics ,Genomic Library ,Sequence analysis ,Hybridization probe ,Molecular Sequence Data ,Genetic Variation ,Nucleic Acid Hybridization ,Genetics and Molecular Biology ,Locus (genetics) ,Sequence Analysis, DNA ,Biology ,Microbiology ,Genome ,Species Specificity ,Genomic island ,Pseudomonas aeruginosa ,Genomic library ,Cloning, Molecular ,Insertion sequence ,Molecular Biology ,Gene ,Genome, Bacterial ,Oligonucleotide Array Sequence Analysis - Abstract
Pseudomonas aeruginosa , a ubiquitous gram-negative bacterium, is capable of colonizing a wide range of environmental niches and can also cause serious infections in humans. In order to understand the genetic makeup of pathogenic P. aeruginosa strains, a method of differential hybridization of arrayed libraries of cloned DNA fragments was developed. An M13 library of DNA from strain X24509, isolated from a patient with a urinary tract infection, was screened using a DNA probe from P. aeruginosa strain PAO1. The genome of PAO1 has been recently sequenced and can be used as a reference for comparisons of genetic organization in different strains. M13 clones that did not react with a DNA probe from PAO1 carried X24509-specific inserts. When a similar array hybridization analysis with DNA probes from different strains was used, a set of M13 clones which carried sequences present in the majority of human P. aeruginosa isolates from a wide range of clinical sources was identified. The inserts of these clones were used to identify cosmids encompassing a contiguous 48.9-kb region of the X24509 chromosome called PAGI-1 (for “ P. aeruginosa genomic island 1”). PAGI-1 is incorporated in the X24509 chromosome at a locus that shows a deletion of a 6,729-bp region present in strain PAO1. Survey of the incidence of PAGI-1 revealed that this island is present in 85% of the strains from clinical sources. Approximately half of the PAGI-1-carrying strains show the same deletion as X24509, while the remaining strains contain both the PAGI-1 sequences and the 6,729-bp PAO1 segment. Sequence analysis of PAGI-1 revealed that it contains 51 predicted open reading frames. Several of these genes encoded products with predictable function based on their sequence similarities to known genes, including insertion sequences, determinants of regulatory proteins, a number of dehydrogenase gene homologs, and two for proteins of implicated in detoxification of reactive oxygen species. It is very likely that PAGI-1 was acquired by a large number of P. aeruginosa isolates through horizontal gene transfer. The selection for its maintenance may be the consequence of expression of any one of the genes of unknown function or the genes which allow P. aeruginosa to survive under the conditions that generate reactive oxygen species. Alternatively, one or both of the transcriptional regulators encoded in PAGI-1 may control the expression of genes in the P. aeruginosa chromosome, which provides a selective advantage for strains that have acquired this genomic island.
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- 2001
- Full Text
- View/download PDF
8. Conservation of genome content and virulence determinants among clinical and environmental isolates of Pseudomonas aeruginosa
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Bridget R. Kulasekara, Kai Wu, Dana Boyd, Matthew C. Wolfgang, Xiaoyou Liang, Qing Yang, C. Garrett Miyada, and Stephen Lory
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DNA, Bacterial ,Washington ,Gene Transfer, Horizontal ,Genetic Vectors ,Virulence ,Fresh Water ,Saccharomyces cerevisiae ,Biology ,medicine.disease_cause ,Genome ,Transformation, Genetic ,Bacterial Proteins ,Genomic island ,medicine ,Humans ,Pseudomonas Infections ,Gene ,Phylogeny ,Oligonucleotide Array Sequence Analysis ,Recombination, Genetic ,Genetics ,Multidisciplinary ,Pseudomonas aeruginosa ,Gene Expression Profiling ,Biological Sciences ,Gene expression profiling ,Horizontal gene transfer ,DNA microarray ,Water Microbiology ,Genome, Bacterial - Abstract
Pseudomonas aeruginosa is a ubiquitous environmental bacterium capable of causing a variety of life-threatening human infections. The genetic basis for preferential infection of certain immunocompromised patients or individuals with cystic fibrosis by P. aeruginosa is not understood. To establish whether variation in the genomic repertoire of P. aeruginosa strains can be associated with a particular type of infection, we used a whole-genome DNA microarray to determine the genome content of 18 strains isolated from the most common human infections and environmental sources. A remarkable conservation of genes including those encoding nearly all known virulence factors was observed. Phylogenetic analysis of strain-specific genes revealed no correlation between genome content and infection type. Clusters of strain-specific genes in the P. aeruginosa genome, termed variable segments, appear to be preferential sites for the integration of novel genetic material. A specialized cloning vector was developed for capture and analysis of these genomic segments. With this capture system a site associated with the strain-specific ExoU cytotoxin-encoding gene was interrogated and an 80-kb genomic island carrying exoU was identified. These studies demonstrate that P. aeruginosa strains possess a highly conserved genome that encodes genes important for survival in numerous environments and allows it to cause a variety of human infections. The acquisition of novel genetic material, such as the exoU genomic island, through horizontal gene transfer may enhance colonization and survival in different host environments.
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- 2003
- Full Text
- View/download PDF
9. VirE1 is a specific molecular chaperone for the exported single-stranded-DNA-binding protein VirE2 in Agrobacterium
- Author
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Wen-Tao Peng, Xiaoyou Liang, Lishan Chen, Milton P. Gordon, Wanyin Deng, Eugene W. Nester, Luca Comai, and Susumu Sekiguchi
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Vesicle-associated membrane protein 8 ,Virulence Factors ,Blotting, Western ,DNA, Single-Stranded ,Sodium Chloride ,Microbiology ,HSPA4 ,Bacterial Proteins ,Yeasts ,HSPA2 ,Protein A/G ,Escherichia coli ,Molecular Biology ,HSPA9 ,biology ,Dose-Response Relationship, Drug ,Models, Genetic ,Sodium Dodecyl Sulfate ,Transport protein ,DNA-Binding Proteins ,Biochemistry ,CDC37 ,Mutagenesis ,Chaperone (protein) ,biology.protein ,Electrophoresis, Polyacrylamide Gel ,Cell Division ,Gene Deletion ,Molecular Chaperones ,Plasmids ,Protein Binding ,Rhizobium - Abstract
Agrobacterium tumefaciens induces tumours on plants by transferring a nucleoprotein complex, the T-complex, from the bacterium to the plant cell. The T-complex consists of a single-stranded DNA (ssDNA) segment, the T-DNA, and VirD2, an endonuclease covalently attached to the 5' end of the T-DNA. A type IV secretion system encoded by the virB operon and virD4 is required for the entry of the T-complex and VirE2, a ssDNA-binding protein, into plant cells. The VirE1 protein is specifically required for the export of the VirE2 protein, as demonstrated by extracellular complementation and tumour formation. In this report, using a yeast two-hybrid system, we demonstrated that the VirE1 and VirE2 proteins interact and confirmed this interaction by in vitro binding assays. Although VirE2 is a ssDNA-binding protein, addition of ssDNA into the binding buffer did not interfere with the interaction of VirE1 and VirE2. VirE2 also interacts with itself, but the interaction between VirE1 and VirE2 is stronger than the VirE2 self-interaction, as measured in a lacZ reporter gene assay. In addition, the interaction of VirE2 with itself is inhibited by VirE1, indicating that VirE2 binds VirE1 preferentially. Analysis of various virE2 deletions indicated that the VirE1 interaction domain of VirE2 overlaps the VirE2 self-interaction domain. Incubation of extracts from Escherichia coli overexpressing His-VirE1 with the extracts of E. coli overexpressing His-VirE2 increased the yield of His-VirE2 in the soluble fraction. In a similar purified protein solubility assay, His-VirE1 increased the amount of His-VirE2 partitioning into the soluble fraction. In Agrobacterium, VirE2 was undetectable in the soluble protein fraction unless VirE1 was co-expressed. When urea was added to solubilize any large protein aggregates, a low level of VirE2 was detected. These results indicate that VirE1 prevents VirE2 from aggregating, enhances the stability of VirE2 and, perhaps, maintains VirE2 in an export-competent state. Analysis of the deduced amino acid sequence of the VirE1 protein revealed that the VirE1 protein shares a number of properties with molecular chaperones that are involved in the transport of specific proteins into animal and plant cells using type III secretion systems. We suggest that VirE1 functions as a specific molecular chaperone for VirE2, the first such chaperone linked to the presumed type IV secretion system.
- Published
- 1999
10. Agrobacterium VirD2 protein interacts with plant host cyclophilins
- Author
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Tracee Metcalfe, Milton P. Gordon, Xiaoyou Liang, Lishan Chen, Wanyin Deng, Eugene W. Nester, Derek W. Wood, and Luca Comai
- Subjects
Genetics ,DNA, Bacterial ,Multidisciplinary ,biology ,Agrobacterium ,Virulence Factors ,Agrobacterium tumefaciens ,Peptidylprolyl Isomerase ,Plants ,Biological Sciences ,biology.organism_classification ,DNA-binding protein ,Cell biology ,chemistry.chemical_compound ,Plasmid ,chemistry ,Bacterial Proteins ,Arabidopsis ,Cyclosporin a ,Arabidopsis thaliana ,DNA ,Plant Proteins ,Protein Binding ,Rhizobium - Abstract
Agrobacterium tumefaciens induces crown gall tumors on plants by transferring a nucleoprotein complex, the T-complex, from the bacterium to the plant cell. The T-complex consists of T-DNA, a single-stranded DNA segment of the tumor-inducing plasmid, VirD2, an endonuclease covalently bound to the 5′ end of the T-DNA, and perhaps VirE2, a single-stranded DNA binding protein. The yeast two-hybrid system was used to screen for proteins interacting with VirD2 and VirE2 to identify components in Arabidopsis thaliana that interact with the T-complex. Three VirD2- and two VirE2-interacting proteins were identified. Here we characterize the interactions of VirD2 with two isoforms of Arabidopsis cyclophilins identified by using this analysis. The VirD2 domain interacting with the cyclophilins is distinct from the endonuclease, omega, and the nuclear localization signal domains. The VirD2–cyclophilin interaction is disrupted in vitro by cyclosporin A, which also inhibits Agrobacterium -mediated transformation of Arabidopsis and tobacco. These data strongly suggest that host cyclophilins play a role in T-DNA transfer.
- Published
- 1998
11. Agrobacterium tumefaciens-mediated transformation of yeast
- Author
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Kevin L. Piers, Kathryn M. Stephens, Eugene W. Nester, Xiaoyou Liang, and Joe Don Heath
- Subjects
Transfer DNA ,DNA, Bacterial ,Virulence Factors ,Saccharomyces cerevisiae ,Genetic Vectors ,DNA, Recombinant ,Biology ,Transfection ,Ti plasmid ,Bacterial Proteins ,DNA, Fungal ,T-DNA Binary system ,Sequence Deletion ,Genetics ,Multidisciplinary ,Virulence ,fungi ,Fungal genetics ,food and beverages ,Agrobacterium tumefaciens ,Telomere ,biology.organism_classification ,Transformation (genetics) ,Genes, Bacterial ,Transformation efficiency ,Research Article - Abstract
Agrobacterium tumefaciens transfers a piece of its Ti plasmid DNA (transferred DNA or T-DNA) into plant cells during crown gall tumorigenesis. A. tumefaciens can transfer its T-DNA to a wide variety of hosts, including both dicotyledonous and monocotyledonous plants. We show that the host range of A. tumefaciens can be extended to include Saccharomyces cerevisiae. Additionally, we demonstrate that while T-DNA transfer into S. cerevisiae is very similar to T-DNA transfer into plants, the requirements are not entirely conserved. The Ti plasmid-encoded vir genes of A. tumefaciens that are required for T-DNA transfer into plants are also required for T-DNA transfer into S. cerevisiae, as is vir gene induction. However, mutations in the chromosomal virulence genes of A. tumefaciens involved in attachment to plant cells have no effect on the efficiency of T-DNA transfer into S. cerevisiae. We also demonstrate that transformation efficiency is improved 500-fold by the addition of yeast telomeric sequences within the T-DNA sequence.
- Published
- 1996
12. Conservation of genome content and virulence determinants among clinical and environmental isolates of Pseudomonas aeruginosa.
- Author
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Wolfgang, Matthew C., Kulasekara, Bridget R., Xiaoyou Liang, Boyd, Dana, Kai Wu, Qing Yang, Miyada, C. Garrett, and Lory, Stephen
- Subjects
PSEUDOMONAS aeruginosa ,PSEUDOMONAS aeruginosa infections ,GENETICS - Abstract
Pseudomonas aeruginosa is a ubiquitous environmental bacterium capable of causing a variety of life-threatening human infections. The genetic basis for preferential infection of certain immunocompromised patients or individuals with cystic fibrosis by P. aeruginosa is not understood. To establish whether variation in the genomic repertoire of P. aeruginosa strains can be associated with a particular type of infection, we used a whole-genome DNA microarray to determine the genome content of 18 strains isolated from the most common human infections and environmental sources. A remarkable conservation of genes including those encoding nearly all known virulence factors was observed. Phylogenetic analysis of strain-specific genes revealed no correlation between genome content and infection type. Clusters of strainspecific genes in the P. aeruginosa genome, termed variable segments, appear to be preferential sites for the integration of novel genetic material. A specialized cloning vector was developed for capture and analysis of these genomic segments. With this capture system a site associated with the strain-specific ExoU cytotoxin-encoding gene was interrogated and an 80-kb genomic island carrying exoU was identified. These studies demonstrate that P. aeruginosa strains possess a highly conserved genome that encodes genes important for survival in numerous environments and allows it to cause a variety of human infections. The acquisition of novel genetic material, such as the exoU genomic island, through horizontal gene transfer may enhance colonization and survival in different host environments. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
13. Identification of a Genomic Island Present in the Majority of Pathogenic Isolates of Pseudomonas...
- Author
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Xiaoyou Liang and Pham, Xuan-Quynh T.
- Subjects
- *
NUCLEOTIDE sequence , *PSEUDOMONAS aeruginosa , *URINARY tract infections , *GENETICS , *PATHOLOGY - Abstract
Reports on the preliminary identification of DNA segments present in a strain of Pseudomonas aeruginosa isolated from a patient with urinary tract infection and absent in strain PAO1. Cloning and sequencing of the pathogen-associated DNA from P. aeruginosa; Sequence analysis and annotation of PAGI-1; Distribution of DNA segments from different isolates.
- Published
- 2001
- Full Text
- View/download PDF
14. Agrobacterium VirD2 protein interacts with plant host cyclophilins.
- Author
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Deng, Wanyin, Chen, Lishan, Wood, Derek W., Metcalfe, Tracee, Xiaoyou Liang, Gordon, Milton P., Comai, Luca, and Nester, Eugene W.
- Subjects
TUMORS ,PLANTS ,AGROBACTERIUM tumefaciens ,NUCLEOPROTEINS - Abstract
Reports on a study which examined the induction of crown gall tumors on plants by the Agrobacterium tumefaciens. Transferral of the T-complex, a nucleoprotein complex from the bacterium to the plant cell; Contents of the T-complex; Methodology used to conduct the study; Results of the study.
- Published
- 1998
- Full Text
- View/download PDF
15. Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C.
- Author
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Kedves, Alexia T., Gleim, Scott, Xiaoyou Liang, Sigoillot, Frederic, Harbinski, Fred, Benander, Christina, George, Elizabeth, Jenkins, Jeremy, Forrester, William C., Bonal, Dennis M., Gokhale, Prafulla C., Nguyen, Quang-De, Kirschmeier, Paul T., Distel, Robert J., Goldberg, Michael S., Sanghavi, Sneha, and Liang, Xiaoyou
- Subjects
- *
UBIQUITIN genetics , *GENE silencing , *GYNECOLOGIC cancer , *DATA analysis , *XENOGRAFTS , *CELL lines , *GENES , *OVARIAN tumors , *PROTEINS , *TUMOR treatment - Abstract
Transcriptional repression of ubiquitin B (UBB) is a cancer-subtype-specific alteration that occurs in a substantial population of patients with cancers of the female reproductive tract. UBB is 1 of 2 genes encoding for ubiquitin as a polyprotein consisting of multiple copies of ubiquitin monomers. Silencing of UBB reduces cellular UBB levels and results in an exquisite dependence on ubiquitin C (UBC), the second polyubiquitin gene. UBB is repressed in approximately 30% of high-grade serous ovarian cancer (HGSOC) patients and is a recurrent lesion in uterine carcinosarcoma and endometrial carcinoma. We identified ovarian tumor cell lines that retain UBB in a repressed state, used these cell lines to establish orthotopic ovarian tumors, and found that inducible expression of a UBC-targeting shRNA led to tumor regression, and substantial long-term survival benefit. Thus, we describe a recurrent cancer-specific lesion at the level of ubiquitin production. Moreover, these observations reveal the prognostic value of UBB repression and establish UBC as a promising therapeutic target for ovarian cancer patients with recurrent UBB silencing. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
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