Ph.D., Syracuse University, 1988
Office: 391 Block Health Science
Phone No: 419.383.4134
My laboratory studies the roles of cytokines in informing physiological changes in both normal and tumor cells. Most of our work has focused on the cellular effects of interferons and, in particular, on the consequences of expression of the interferon-induced proteins of the Guanylate-Binding Protein (GBP) family.
Guanylate-Binding Proteins (GBPs)
The GBPs are members of the dynamin superfamily of large GTPases. Unlike members of the Ras superfamily, these proteins can multimerize and their multimerization is both nucleotide-dependent and accelerates GTP hydrolysis. Some of the GBPs contain C-terminal CaaX sequences that direct isoprenylation. Our recent studies of the murine family member, mGBP-2, show that mGBP-2 induction by IFN-γ in fibroblasts inhibits subsequent activation of Rac by integrins, PDGF, and TNF-α. mGBP-2 mediated inhibition of Rac results in retarded ability of the cells to spread on fibronectin. This inhibition of cell spreading is also accompanied by an inhibition of the activation of PI3-K, during which mGBP-2 binds to the p110 catalytic subunit of PI3-K. The IFN-γ-induced expression of mGBP-2 also inhibits the induction of MMP-9 expression by TNF-α. mGBP-2 facilitates this inhibition by inhibiting both NF-κB promoter binding and Rac activation. Work is currently in progress to delineate the mechanisms by which mGBP-2 inhibits PI3-K, Rac, and NF-κB.
The human GBP, hGBP-1, is part of a gene signature predicting good disease free progression in breast cancer. Work is currently underway to determine how hGBP-1 improves breast cancer survival.
Wadi, S., Tipton, A.R., Trendel, J.A., Khuder, S.A., and Vestal, D.J. (2016). hGBP-1 expression predicts shorter progression-free survival in ovarian cancers, while contributing to paclitaxel resistance. J. Cancer Therapy 7: 994-1007.
Tipton, A.R., Nyabuto, G.O., Trendel, J.A., Mazur, T.M., Wilson, J.P., Wadi, S., Justinger, J.S., Moore, G.L., Nguyen, P.T., and Vestal, D.J. (2016). Guanylate-Binding Protein-1 protects ovarian cancer cell lines but not breast cancer cell lines from killing by paclitaxel. Biochem. Biophys. Res. Commun. 478: 1617-1623.
Balasubramanian, S., Fan, M., Messmer-Blust, A.F., Yang, C.H., Trendel, J.A., Jeyaratnam, J.A., Pfeffer, L.M., and Vestal, D.J. (2011) The Interferon-γ-induced GTPase, mGBP-2, inhibits Tumor Necrosis Factor α (TNF-α) induction of Matrix Metalloproteinase-9 (MMP-9) by inhibiting NF-κB and Rac. J. Biol. Chem. 286: 20054-20064.
Balasubramanian, S*., Messmer-Blust, A.F*., Jeyaratnam, J.A., and Vestal, D.J. (2011) Role of GTP binding, isoprenylation, and the C-terminal α-helices in the inhibition of cell spreading by the IFN-induced GTPase, mGBP-2. Journal Interferon Cytokine Res. 31: 291-298. * Authors contributed equally.
Vestal, D.J., and Jeyaratnam, J.A. (2010) The Guanylate-Binding Proteins (GBPs): Emerging insights into the biochemical properties and functions of this family of large interferon-induced GTPases. J. Interferon Cytokine Res. 31: 89-97. PMCID: PMC3021356
Messmer-Blust, A.F., Balasubramanian, S., Gorbacheva, V.Y., Jeyaratnam, J.A., and
Vestal, D.J. (2010) The interferon-γ-induced murine Guanylate-Binding Protein-2 (mGBP-2) inhibits
Fibronectin and PDGF-dependent Rac activation during cell spreading: role for Phosphatidylinositol
3-kinase (PI3-K). Mol. Biol. Cell, 21: 2514-2528. PMCID: PMC2903678
Editors choice for the topic of cell biology in Science Signaling. Review
of the manuscript: Nancy R. Gough (2010) “Interferon-γ inhibits cell
spreading by increasing the abundance of an unusual guanosine
triphosphatase, GBP-2, that inhibits phosphoinositide 3-kinase.
Science Signaling 3: ec221. http//stke.sciencemag.org/content
Olszewski, M. A., Gray, J., and Vestal, D.J. (2006). In silico genomic analysis of the human and murine guanylate binding protein (GBP) gene clusters. J. Interferon Cytokine Res. 26: 328-352.
Balasubramian, S., Nada, S., and Vestal, D.J. (2006). The interferon-induced GTPase, mGBP-2, confers resistance to paclitaxel-induced cytotoxicity without inhibiting multinucleation. Cellular and Molecular Biology 52: 43-49.
Vestal, D.J. (2005). The guanylate binding proteins (GBPs): Pro-inflammatory cytokine-induced members of the dynamin superfamily with unique GTPase activity. J. Interferon Cytokine Res. 25: 435-443.
Carter, C., Gorbacheva, V.Y., and Vestal, D.J. (2005). Inhibition of VSV and EMCV replication by the interferon-induced GTPase, mGBP-2: Differential requirement for wild-type GTP binding domain. Arch. Virol.150:1213-1220.
Gorbacheva, V.Y., Lindner, D., Sen, G.C., and Vestal, D.J. (2002). The interferon (IFN)-induced GTPase, mGBP-2: Role in IFN-γ-induced murine fibroblast proliferation. J. Biol. Chem. 277: 6080-6087. Free article.
Vestal, D.J., Gorbacheva, V.Y., and Sen, G.C. (2000). Different subcellular localizations for the related interferon-induced GTPases, mGBP-1 and mGBP-2: Implications for different functions? J. Interferon Cytokine. Res. 20: 991-1000.
Vestal, D.J., Buss, J.E., McKercher, S.R., Jenkins, N.A., Copeland, K.G., Kelner, G. S., Asundi, V.K. and Maki, R.A. (1998). Murine GBP-2: A new IFN-g-induced member of the GBP family of GTPases from macrophages. J. Interferon and Cytokine Res. 18: 977-985.
Balasubramanian, S., Olszewski, M.A., and Vestal, D.J. (2007). Interferon-induced GTPases: Composition of gene families and role in interferon responses. In: Interferons: Current Status. Research Signposts. Chadka, K., ed. Pages 69-95.
Vestal, D.J., Yi, T., Borden, E.C. (2001). Pharmacology of Interferons: Induced Proteins, Cell Activation, and Antitumor Activity. In: Cancer Chemotherapy and Biotherapy: Principles and Practice. Third Edition. Chabner, B.A. and Longo, D.L., ed. Lippencott, Williams, and Wilkins, publisher. Pages 752-778.