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2009 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report Arthur S. Alberts, Ph.D. Laboratory of Cell Structure and Signal Integration In 1993, Dr. Art Alberts received his Ph.D. in Physiology and Pharmacology at the University of California, San Diego School of Medicine, where he studied with Jim Feramisco. Dr. Alberts trained as a postdoctoral fellow from 1994 to 1997 with Richard Treisman at the Imperial Cancer Research Fund in London, England, where Dr. Treisman is the current Director. From 1997 through 1999, Dr. Alberts was an Assistant Research Biochemist in the laboratory of Frank McCormick at the University of California, San Francisco. In January 2000, Dr. Alberts joined VARI as a Scientific Investigator; he was promoted in 2006 to Senior Scientific Investigator. Also in 2006, he established and became the Director of the Flow Cytometry core facility. Staff Students Visiting Scientists Kathryn Eisenmann, Ph.D. Leanne Lash-Van Wyhe, Ph.D. Richard A. West, M.S. Susan Kitchen, B.S. Debra Guthrey Kellie Leali Aaron DeWard, B.S. Jonathan Rawson Albert Rodriguez Sara Sternberger Katja Strunk Stephen Matheson, Ph.D. Brad Wallar, Ph.D. 8

VARI | 2009 Research Interests The Laboratory of Cell Structure and Signal Integration is devoted to understanding how defects in cellular architecture affect the progression to malignancy and support the tumorigenic platform. The driving hypothesis is that the cytoskeleton does not only structurally support cell morphology, division, and migration, but with its dynamic nature, it organizes intracellular signaling networks in order to effectively interpret proliferative and migratory responses to extracellular cues. On a molecular basis, we are interested in how cells build and control the cytoskeletal assembly machines and how these molecular machines work in concert within the cell. Through combined molecular, cellular, and genetic approaches, the ultimate goal of the lab is identifying defective nodes in the networks governing cytoskeletal remodeling in order to improve diagnosis and devising molecular tools to correct the defective circuits. Our focus is the role of Rho GTPases in signal transduction networks that control cell proliferation and motility. These highly conserved molecular switches act within growth factor responses by alternating between GTP- and GDP-bound forms. Upon GTP binding, Rho proteins undergo a conformational change that allows them to bind to and modulate the activity of effectors that remodel cell shape, drive motility and division, or alter gene expression patterns. One set of GTPase effector proteins acts as machines that assemble components of the cytoskeleton. The mammalian Diaphanous-related formin (mDia) family of actinnucleating proteins initiate and control the elongation of new actin filaments. The three conserved mDia proteins (mDia1–3), along with insect Diaphanous protein and their budding yeast counterpart Bni1p, are canonical members of the formin family. With our discovery of one of the first formin proteins, mDia2, we have taken a leading role in their characterization. To study the role of mDia1 in vivo, the murine Drf1 gene was knocked out by conventional gene-targeting methods. Both Drf1 +/– and Drf1 –/– mice become progressively lympho- and myelodysplastic. Drf1-targeted mice are prone to developing tumors; cancers observed thus far include various leukemias, monocytosis, and plasmocytomas. Overall, mice lacking one or both Drf1 alleles phenocopy human myelodysplastic syndrome. Numerous defects in cytoskeletal remodeling have been observed in immune cells, including impaired T cell adhesion, impaired migration, and the appearance of supernumerary centrosomes, which are indicative of failed cell division. These results have been published in the Journal of Biological Chemistry, Cancer Research, and Oncogene. Overall, the mDia1 knock-out phenotype resembles human chronic myeloproliferative syndrome (MPS) and myelodysplastic syndrome (MDS). Both MPS and MDS have been characterized as preleukemic states, with variable lymphopenia, excess or dysfunctional erythrocytes, chronic myelomonocytic leukemia, ineffective hematopoiesis, and, in some cases, advancing myelofibrosis. Instances of neutrophilic dermatoses (Sweet syndrome) can also accompany MDS and MPS. MDS is a frequent hematologic disorder that typically affects older patients and is thought to be a stem cell disorder. Dysplastic features of the nucleus or cytoplasm, as observed in the mDia1 knock-out mice, and altered cellularity of the bone marrow are also characteristic of MDS. The effect of Drf1 gene targeting and the resulting mDia1 knock-out suggests that the DRF1 gene for human mDia1 is affected in MPS, MDS, or other preleukemic pathologies. Ongoing studies are focused on examining if defects in the human gene encoding mDia1 might be defective in MDS patients. 9

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