 |
Thomas
M. Guadagno, Ph.D. E-mail:
Thomas.Guadagno@moffitt.org |
Training
B.S. University of Rochester
Ph.D. Columbia University
Postdoctoral Fellow, University of California, San Diego
Postdoctoral Fellow, Stanford University
Research Interests
Signal transduction pathways that regulate cell division, mitotic checkpoint controls and, mechanisms of tumor progression.
Research Summary
Our laboratory is interested in unraveling the biochemical controls that regulate cell division. Of particular interest is determining the signaling pathways that regulate the mitotic spindle apparatus- a critical structure that coordinates the equal segregation of chromosome copies into two daughter cells. Errors in the events that mediate cell division can lead to chromosome abnormalities (such as aneuploidy) that contribute to tumorigenesis.
Presently, the Guadagno lab is addressing the role of microtubule-activated protein kinase (MAPK) pathway during mitosis. The lab uses the Xenopus egg extract model system as well as mammalian tissue culture cells to interfere with MAPK function at mitosis and ask what the consequences are on the mitotic spindle. A recent publication from our lab shows that MAPK is absolutely required for regulating the assembly and stability of the mitotic spindle (Horne and Guadagno, JCB 2003). Studies are in progress to identify the key MAPK targets that directly link its role in regulating the mitotic spindle. A second area of focus in the laboratory is elucidating the upstream regulators that control activation of the MAPK cascade during mitosis. To this end, we have discovered that B-Raf (MAPK kinase kinase) serves this important role. Loss-of-function studies demonstrate that B-Raf is absolutely required for MAPK activation at mitosis. Since the B-raf gene is activated by point mutations in many types of cancer- most profoundly in skin cancer (65% Melanomas), we are interested in elucidating how oncogenic activation of B-Raf contributes to deregulation of cell proliferation and cancer.
Finally, our lab studies a protein called Survivin that is one of the most widely overexpressed proteins in cancer. Studies support a bifunctional role for Survivin as an essential regulator of mitosis and as an anti-apoptotic regulator that promotes tumor survival. Normally, Survivin is expressed at very low levels in cells that actively proliferate. The molecular basis for Survivin's function at mitosis and in tumor survival is unknown. To begin to understand theses mechanisms, our lab has identified several Survivin-interacting candidates that will allow us to address these questions.
Overall, the long-term goals of our lab are to understand how chromosome abnormalities arise in cancer and establish feasible targets in cancer that novel therapies can be developed.
Search
for publications by: 
This
search will be conducted at the US National Library of Medicine (NLM) and PubMed.
Selected
Publications
Guadagno, T. and J.E. Ferrell, Jr. Requirement for MAPK activation for
normal mitotic progression in Xenopus mitotic egg extracts. Science 282:
1312-1315. 1998.
Melinda M. Horne and Thomas M. Guadagno. A Requirement for MAP kinase in the Assembly and Maintenance of the Mitotic Spindle. J. Cell Biology 161:1-21-1028. 2003.
Sergiy I. Borysov and Thomas M. Guadagno. B-Raf is for MAPK signaling during mitosis. (Submitted).
Pedro Canovas
and Thomas M. Guadagno. The absence of Survivin function leads to a 'mini
spindle' phenotype is Xenopus egg extracts. (in preparation)
Cancer Biology Ph.D. Program
H. Lee Moffitt Cancer Center, MRC-4 East
12902 Magnolia Drive
Tampa, Florida 33612
Phone: 813-745-6876
E-mail: CancerPHD@moffitt.org
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