Section: Rotations

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Stephen Doxsey, Ph.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Program in Molecular Medicine

Joint Faculty In:
   Biochemistry and Molecular Pharmacology

Other Affiliation(s):
   Cell Biology
   Cell Dynamics Group
   Interdisciplinary Graduate Program

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.

Office: Biotech II-Suite 210
Phone: 508-856-1613
E-mail: Stephen.Doxsey@umassmed.edu
Keywords: Cancer Biology, Cell Biology, Biochemistry

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