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2006 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report Research Interests The overall goal of the Laboratory of Cancer and Developmental Cell Biology is to advance the study of mitogen-activated protein kinase kinase (MEK) signaling in health and disease. Currently, work performed in the lab is organized into three projects to explore 1) MEK signaling and tumor biology, 2) the therapeutic potential of anthrax lethal toxin (LeTx), and 3) molecular mechanisms of anthrax lethal toxin action. MEK signaling and tumor biology Many malignant sarcomas such as angiosarcomas are refractory to currently available treatments. However, sarcomas possess unique vascular properties which indicate they may be more responsive to therapeutic agents that target endothelial function. MEKs have been demonstrated to play an essential role in the growth and vascularization of carcinomas. We hypothesize that signaling through multiple MEK pathways is also essential for sarcoma growth and vascularization. The objective of this research is to define the role of MEK signaling in the growth and vascularization of human sarcoma and to determine whether inhibition of multiple MEKs by agents such as LeTx, a proteolytic inhibitor of MEKs, may form the basis of a novel and innovative approach in the treatment of human sarcoma. The therapeutic potential of anthrax lethal toxin 18 Data from the National Cancer Institute’s Anti-Neoplastic Drug Screen indicates that several tumor types, notably melanomas and colorectal adenocarcinomas, are sensitive to LeTx. In addition, we have noted that angio-proliferative tumors are also very sensitive to LeTx treatment. Consequently we have undertaken a systematic evaluation of the effects of LeTx upon human tumor-derived melanoma, colorectal adenocarcinoma, and Kaposi sarcoma cell lines. The goal of this project is to develop novel therapeutic agents that may be efficacious in the treatment of human malignancies. In collaboration with Art Frankel at Scott & White Memorial Hospital Cancer Research Institute in Temple, Texas, we have begun a project to manufacture clinical-grade LeTx. The first results of these studies were published this year in Molecular Cancer Therapeutics. Molecular mechanisms of anthrax LeTx action The lethal effects of Bacillus anthracis have been attributed to an exotoxin which it produces. This exotoxin is composed of three proteins: protective antigen (PA), edema factor (EF), and lethal factor (LF). EF is an adenylate cyclase and together with PA forms a toxin referred to as edema toxin. LF is a Zn 2+ -metalloprotease which together with PA forms a toxin referred to as lethal toxin (LeTx). LeTx is the dominant virulence factor produced by B. anthracis and is the major cause of death in infected animals. The goal of this project is to develop a detailed molecular understanding of LF function that will improve our understanding of the biology underlying anthrax. Lab notes This year our lab welcomed two new postdoctoral fellows, Philippe Depeille and Yan Ding, who will be studying the role of MEK signaling in vascularization and the growth of Kaposi sarcoma and fibrosarcoma, respectively. Hilary Wagner and David Slager joined the lab as technicians. Each will perform molecular studies of anthrax toxin function in tissue culture and in mice. Two new students also joined our lab this year. Chih-Shia Lee is a graduate student who, along with Zafar Qadir, a visiting student from the University of Bath, is investigating MEK function in cells following exposure to LeTx. As well, we hosted Courtney Banks and Anna Fairchild, two Grand Rapids area high school students interested in careers in biological research. Courtney and Anna evaluated the sensitivity of macrophage cells to LeTx. Paul Spilotro, a postdoctoral fellow who joined us in 2004, moved on to do his medical residency at Spectrum Health in Grand Rapids.

VARI | 2006 19 Recent Publications From left: Holman, Lee, Duesbery, Depeille, Young, Qadir, Ding, Boguslawski Duesbery, Nick, and George Vande Woude. 2006. BRAF and MEK mutations make a late entrance. Science’s STKE 328: pe15. Abi-Habib, Ralph J., Jeffrey O. Urieto, Shihui Liu, Stephen H. Leppla, Nicholas S. Duesbery, and Arthur E. Frankel. 2005. BRAF status and mitogen-activated protein/extracellular signal–regulated kinase kinase 1/2 activity indicate sensitivity of melanoma cells to anthrax lethal toxin. Molecular Cancer Therapeutics 4(9): 1303–1310. Bodart, J.-F.L., F.Y. Baert, C. Sellier, N.S. Duesbery, S. Flament, and J.-P. Vilain. 2005. Differential roles of p39 Mos -Xp42 Mpk1 cascade proteins on Raf1 phosphorylation and spindle morphogenesis in Xenopus oocytes. Developmental Biology 283(2): 373–383. Bodart, Jean-François L., and Nicholas S. Duesbery. 2005. Xenopus tropicalis oocytes: more than just a beautiful genome. In Xenopus Protocols: Cell Biology and Signal Transduction, X.J. Liu, ed. Methods in Cell Biology series, Totowa, N.J.: Humana Press.

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