University of South Florida

Cancer Biology Ph.D. Program at the

Thomas M. Guadagno, Ph.D. Assistant Professor in the Department of Oncologic Sciences Member-in-Residence of the Moffitt Cancer Center E-mail: Thomas.Guadagno@moffitt.org Phone: (813)-745-6818

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

Borysov SI, Guadagno TM.A Novel Role for Cdk1/cyclin B in Regulating B-Raf Activation at Mitosis.Mol Biol Cell. 2008 Apr 23. [Epub ahead of print]

Cui Y, Guadagno TM.B-Raf(V600E) signaling deregulates the mitotic spindle checkpoint through stabilizing Mps1 levels in melanoma cells.Oncogene. 2008 May 15;27(22):3122-33. Epub 2007 Dec 10

Canovas PM, Guadagno TM.Functional analysis of Survivin in spindle assembly in Xenopus egg extracts.J Cell Biochem. 2007 Jan 1;100(1):217-29.

Borysov SI, Cheng AW, Guadagno TM.B-Raf is critical for MAPK activation during mitosis and is regulated in an M phase-dependent manner in Xenopus egg extracts.J Biol Chem. 2006 Aug 11;281(32):22586-96. Epub 2006 Jun 8.

Horne MM, Guadagno TM.A requirement for MAP kinase in the assembly and maintenance of the mitotic spindle.J Cell Biol. 2003 Jun 23;161(6):1021-8.

Guadagno TM, Ferrell JE Jr.Requirement for MAPK activation for normal mitotic progression in Xenopus egg extracts.Science. 1998 Nov 13;282(5392):1312-5.