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Search Results to Stephen John Doxsey PhD

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Academic Background

Stephen Doxsey received his BS from the University of Connecticut in 1977 and his PhD in Cell Biology from Yale University in 1987. He was awarded Anna Fuller and Damon Runyon Fellowships during his postdoctoral training in Dr. Marc Kirschner's laboratory at the University of California at San Francisco. Dr. Doxsey joined the faculty at the University of Massachusetts Medical School in the Program in Molecular Medicine in 1993.

Regulation of Mitotic Spindle Assembly

Steve DoxseyMicrotubules are required for such fundamental cellular processes as cell division, embryogenesis, cell motility and organelle translocation. In all animal cells, the microtubule cytoskeleton arises from the centrosome, an organelle with the ability to nucleate microtubules.

This laboratory is interested in understanding how the centrosome organizes microtubule arrays such as the mitotic spindle. We have cloned and characterized pericentrin, a highly conserved centrosome protein essential for cell division and microtubule organization. Pericentrin forms a large complex with gamma tubulin and other proteins involved in microtubule nucleation. Expression of mutated forms of pericentrin in cells induces the formation of 'ectopic centrosomes' that nucleate microtubules. Current work involves expression of chimeras of pericentrin and green fluorescent protein to monitor centrosome dynamics and function in living cells. In collaboration with the Biomedical Imaging Group, who developed new superresolution immunofluorescence technology, we discovered that centrosomes are comprised of a novel lattice structure (see Figure A). The mechanism and regulation of centrosome assembly is being investigated using in vitro reconstitution systems and in vivo systems developed in our laboratory. Centrosome assembly in mammalian cells is microtubule-dependent and mediated by the molecular motor, dynein. We are characterizing other highly conserved, novel centrosome proteins identified with serum from patients with the autoimmune disease, scleroderma. Finally, we recently discovered that pericentrin is overexpressed in tumors and that tumor cells have abnormal centrosomes, suggesting a possible role of pericentrin in tumorigenesis.

Figure

Research Figure A.


A. Immunofluorescence image of microtubules (red) grown from a centrosome (yellow). The centrosome was stained with antibodies to pericentrin, a highly conserved and essential centrosome protein. The novel centrosome lattice revealed in this image was discovered using imaging technology recently developed by Dr. Fred Fay and coworkers here at UMass.

Rotation Projects

Potential Rotation Projects:

Project #1: Centrosomes, chromosome segregation and cancer. We have shown that the assembly of centrosomes is essential for spindle function (Zimmerman et al., 1999, 2000; Doxsey, 2001). We recently discovered that centrosomes assemble by an unexpected mechanism involving the molecular motor cytoplasmic dynein (Young et al, 2000; Tynan et al., 2000). This mechanism is mediated by a direct interaction between the essential centrosome protein pericentrin (Doxsey et al., 1994; Dictenberg et al., 1998) and the dynein light intermediate chain (Purohit et al., 1999; Tynana et al., 2000). Moreover, pericentrin interacts with many proteins including the g tubulin complex, which nucleates microtubules (Dictenberg et al., 1998; Diviani et al., 2000). Centrosome assembly is disrupted in human cancer--nearly all malignant tumors have aberrant centrosomes (Pihan et al., 1998, Doxsey, 1999). To our surprise, most tumor cells overexpress pericentrin and artificial overexpression of pericentrin in normal cells induces a cancer-like phenotype (Purohit et al., 1999; Pihan et al., 2000, 2001). Projects:

  1. Determine how centrosome assembly is regulated.
  2. Determine the role of the pericentrin-dynein interaction in spindle organization.
  3. Test how increased pericentrin levels and centrosome defects contribute to cancer.
  4. Identify novel pericentrin-binding proteins.
  5. Determine how pericentrin levels and functions are regulated.
  6. Determine how pericentrin binds and transports g tubulin complexes to centrosomes.

Project #2: Mechanism of autoantibody production in autoimmunity. Centrosomes are targeted by autoantibodies in the human autoimmune disease scleroderma (Gavanescu et al., 1999), although the mechanism is unknown. We recently discovered that centrosome autoantibodies can be induced an infectious agent (Gavanescu et al., in prep). PCR analysis demonstrated ectopic localization of this organism to skin lesions of scleroderma patients but not controls. These results suggest that this agent contributes to autoantibody development, disease pathogenesis and immune dysfunction in scleroderma patients. Projects:

  1. Determine the mechanism of autoantibody production in mice mutant for immune components.
  2. Test whether centrosome autoreactivity precedes other autoantibodies (anti-nuclear).
  3. Determine if this agent is present in other autoimmune diseases.
  4. Determine if the pathological symptoms of scleroderma are alleviated following treatment of the agent.

One or more keywords matched the following items that are connected to Doxsey, Stephen

Item TypeName
Academic Article Pericentriolar targeting of GDP-dissociation inhibitor isoform 2.
Academic Article Phosphorylation of NUMA occurs during nuclear breakdown and not mitotic spindle assembly.
Academic Article Centrosomal deployment of gamma-tubulin and pericentrin: evidence for a microtubule-nucleating domain and a minus-end docking domain in certain mouse epithelial cells.
Academic Article Nucleation and capture of large cell surface-associated microtubule arrays that are not located near centrosomes in certain cochlear epithelial cells.
Academic Article Rapid isolation of centrosomes.
Academic Article Functional analysis of Tpr: identification of nuclear pore complex association and nuclear localization domains and a role in mRNA export.
Academic Article Direct interaction of pericentrin with cytoplasmic dynein light intermediate chain contributes to mitotic spindle organization.
Academic Article Pericentrin anchors protein kinase A at the centrosome through a newly identified RII-binding domain.
Academic Article Heat shock causes protein aggregation and reduced protein solubility at the centrosome and other cytoplasmic locations.
Academic Article Cytoplasmic dynein-mediated assembly of pericentrin and gamma tubulin onto centrosomes.
Academic Article Light intermediate chain 1 defines a functional subfraction of cytoplasmic dynein which binds to pericentrin.
Academic Article Mitochondrial association of a plus end-directed microtubule motor expressed during mitosis in Drosophila.
Academic Article Cell cycle independent interaction of CDC2 with the centrosome, which is associated with the nuclear matrix-intermediate filament scaffold.
Academic Article Pericentrin and gamma-tubulin form a protein complex and are organized into a novel lattice at the centrosome.
Academic Article The centrosome--a tiny organelle with big potential.
Academic Article A novel human protein of the maternal centriole is required for the final stages of cytokinesis and entry into S phase.
Academic Article Centrosome dynamics in living cells.
Academic Article Mitosis-specific anchoring of gamma tubulin complexes by pericentrin controls spindle organization and mitotic entry.
Academic Article Pericentrin forms a complex with intraflagellar transport proteins and polycystin-2 and is required for primary cilia assembly.
Academic Article Centrosome proteins: a major class of autoantigens in scleroderma.
Academic Article Membrane type-1 matrix metalloproteinase (MT1-MMP) exhibits an important intracellular cleavage function and causes chromosome instability.
Academic Article Centrosomes in cellular regulation.
Academic Article Centriolin anchoring of exocyst and SNARE complexes at the midbody is required for secretory-vesicle-mediated abscission.
Academic Article Survivin modulates microtubule dynamics and nucleation throughout the cell cycle.
Academic Article Construction of centrosomes and spindle poles by molecular motor-driven assembly of protein particles.
Academic Article Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network.
Academic Article Methods for the study of pericentrin in centrosome assembly and function.
Academic Article CSPP is a ciliary protein interacting with Nephrocystin 8 and required for cilia formation.
Academic Article The cilia protein IFT88 is required for spindle orientation in mitosis.
Academic Article Midbody accumulation through evasion of autophagy contributes to cellular reprogramming and tumorigenicity.
Academic Article Centrin depletion causes cyst formation and other ciliopathy-related phenotypes in zebrafish.
Academic Article Orchestrating vesicle transport, ESCRTs and kinase surveillance during abscission.
Academic Article Clathrin promotes centrosome integrity in early mitosis through stabilization of centrosomal ch-TOG.
Academic Article The centrosome regulates the Rab11- dependent recycling endosome pathway at appendages of the mother centriole.
Academic Article Multiplying madly: deacetylases take charge of centrosome duplication and amplification.
Academic Article Duplicating dangerously: linking centrosome duplication and aneuploidy.
Academic Article Resurrecting remnants: the lives of post-mitotic midbodies.
Academic Article One among many: ODF2 isoform 9, a.k.a. Cenexin-1, is required for ciliogenesis.
Academic Article An efficient method for introducing macromolecules into living cells.
Academic Article Inhibition of endocytosis by anti-clathrin antibodies.
Academic Article The Drosophila kinesin-like protein KLP67A is essential for mitotic and male meiotic spindle assembly.
Academic Article Centrosomal anchoring of protein kinase C betaII by pericentrin controls microtubule organization, spindle function, and cytokinesis.
Academic Article Thermotolerant cells possess an enhanced capacity to repair heat-induced alterations to centrosome structure and function.
Academic Article Pericentrin, a highly conserved centrosome protein involved in microtubule organization.
Academic Article Molecular links between centrosome and midbody.
Academic Article Latent membrane protein 1 suppresses RASSF1A expression, disrupts microtubule structures and induces chromosomal aberrations in human epithelial cells.
Academic Article The DNA helicase ChlR1 is required for sister chromatid cohesion in mammalian cells.
Academic Article Loss of centrosome integrity induces p38-p53-p21-dependent G1-S arrest.
Academic Article Chromatin remodeling proteins interact with pericentrin to regulate centrosome integrity.
Academic Article Genetics. Dwarfism, where pericentrin gains stature.
Academic Article Id1 overexpression induces tetraploidization and multiple abnormal mitotic phenotypes by modulating aurora A.
Academic Article A last-minute rescue of trapped chromatin.
Academic Article Dynein light intermediate chain 1 is required for progress through the spindle assembly checkpoint.
Academic Article Delivery of macromolecules into cells expressing a viral membrane fusion protein.
Academic Article Fates and roles of post-mitotic midbodies beyond cytokinesis.
Academic Article Polarity sets the stage for cytokinesis.
Academic Article Both viral (adenovirus E1B) and cellular (hsp 70, p53) components interact with centrosomes.
Concept Vesicular Transport Proteins
Concept Membrane Proteins
Concept Protein Binding
Concept Protein Transport
Concept Protein Folding
Concept Protein Processing, Post-Translational
Concept Heat-Shock Proteins
Concept Tumor Suppressor Protein p53
Concept Nuclear Pore Complex Proteins
Concept p38 Mitogen-Activated Protein Kinases
Concept HSP70 Heat-Shock Proteins
Concept Inhibitor of Differentiation Protein 1
Concept GTP-Binding Proteins
Concept Adenovirus E1B Proteins
Concept Carrier Proteins
Concept Chromosomal Proteins, Non-Histone
Concept Cell Cycle Proteins
Concept Luminescent Proteins
Concept CDC2 Protein Kinase
Concept Nuclear Proteins
Concept Recombinant Proteins
Concept Cyclic AMP-Dependent Protein Kinases
Concept Protein-Serine-Threonine Kinases
Concept Intracellular Signaling Peptides and Proteins
Concept Viral Proteins
Concept Repressor Proteins
Concept HSP90 Heat-Shock Proteins
Concept rab GTP-Binding Proteins
Concept Protein Kinase C
Concept Nuclear Matrix-Associated Proteins
Concept Proteins
Concept Zebrafish Proteins
Concept Microtubule-Associated Proteins
Concept Protein Structure, Secondary
Concept rab3 GTP-Binding Proteins
Concept Cytoskeletal Proteins
Concept Protein Structure, Tertiary
Concept Adaptor Proteins, Signal Transducing
Concept Proto-Oncogene Proteins c-myc
Concept Ubiquitin-Protein Ligase Complexes
Concept Green Fluorescent Proteins
Concept Recombinant Fusion Proteins
Concept Calcium-Binding Proteins
Concept Inhibitor of Apoptosis Proteins
Concept Protein Stability
Concept Fungal Proteins
Concept Saccharomyces cerevisiae Proteins
Concept Neoplasm Proteins
Concept Drosophila Proteins
Concept Microfilament Proteins
Concept Microtubule Proteins
Concept Cyclic AMP-Dependent Protein Kinase Type II
Concept rab5 GTP-Binding Proteins
Concept RGS Proteins
Concept Viral Matrix Proteins
Concept Viral Fusion Proteins
Concept Molecular Motor Proteins
Concept Protein Isoforms
Concept Proto-Oncogene Proteins
Concept Tumor Suppressor Proteins
Concept RNA-Binding Proteins
Academic Article Rab11 endosomes contribute to mitotic spindle organization and orientation.
Academic Article A new role for Rab GTPases during early mitotic stages.
Academic Article Characterization of the human NEK7 interactome suggests catalytic and regulatory properties distinct from those of NEK6.
Academic Article A unique set of centrosome proteins requires pericentrin for spindle-pole localization and spindle orientation.
Academic Article CPEB regulation of TAK1 synthesis mediates cytokine production and the inflammatory immune response.
Academic Article The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.
Academic Article Human Nek7-interactor RGS2 is required for mitotic spindle organization.
Academic Article Centrosome-intrinsic mechanisms modulate centrosome integrity during fever.
Academic Article New frontiers: discovering cilia-independent functions of cilia proteins.
Academic Article Viruses as tools in drug delivery.
Academic Article The Mother Centriole Appendage Protein Cenexin Modulates Lumen Formation through Spindle Orientation.
Academic Article Multipolar mitosis and aneuploidy after chrysotile treatment: a consequence of abscission failure and cytokinesis regression.
Academic Article The Mother Centriole Appendage Protein Cenexin Modulates Lumen Formation through Spindle Orientation.

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  • GTP Binding Proteins