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2002 Scientific Report

  • Text
  • Institute
  • Report
  • Tumors
  • Protein
  • Signaling
  • Michigan
  • Molecular
  • Proteins
  • Laboratory

External Collaborators

External Collaborators Catherine Fox, University of Wisconsin–Madison Chun Liang, Hong Kong University Publications Weinreich, Michael, Chun Liang, Hsu-Hsin Chen, and Bruce Stillman. 2001. Binding of cyclindependent kinases to ORC and Cdc6p regulates the chromosome replication cycle. Proceedings of the National Academy of Sciences U.S.A. 98(20): 11211–11217. From left to right: Mynsberge, Weinreich, Russo, Gabrielse, Pappas, Blokhin 55

Laboratory of Cell Signaling and Carcinogenesis Bart O. Williams, Ph.D. Dr. Williams received his Ph.D. in biology from Massachusetts Institute of Technology in 1996. For three years, he was a Postdoctoral Fellow at the National Institutes of Health in the laboratory of Harold Varmus, former Director of NIH. Dr. Williams joined VARI as a Scientific Investigator in July 1999. Staff Troy Giambernardi, Ph.D. Sheri Holmen, Ph.D. Scott Robertson, B.S. Cassandra Zylstra, B.S. Laboratory Members Students Holli Charbonneau Jennifer Daugherty Jennifer Mieras Research Projects Our laboratory is focused on understanding how alterations in the Wnt signaling pathway cause human disease. Alterations in the pathway are among the most common changes associated with human cancer and have also been linked to other disorders, including osteoporosis. A very complete overview of this pathway can be found on a Web site (http://www.stanford.edu/~rnusse/wntwindow.html) developed by Dr. Roel Nusse. We are particularly interested in elucidating the mechanisms by which the secreted Wnt ligand activates the pathway by binding to the receptor complex at the plasma membrane. Wnt binds to a receptor complex that includes a member of the frizzled family and LRP5 or LRP6. The activation of this complex then inhibits the targeting of β-catenin and plakoglobin for ubiquitin-dependent proteolysis. This inhibition results in the accumulation of these proteins in the cytosol, where they interact with the LEF/TCF family of DNA binding proteins and subsequently translocate to the nucleus where they alter gene expression. In other contexts, Wnt ligands can activate protein kinase C or Rho-dependent pathways. There are many levels of regulating the reception of Wnt signals. The completion of the human genome project has shown that there are 19 different genes that encode Wnt proteins, 9 encoding Frizzled proteins, and two LDL receptor–related proteins that function in Wnt signaling (LRP5 and LRP6). In addition, there are several proteins that can inhibit Wnt signaling by binding to components of the receptor complex and interfering with normal signaling (Figure 1). These include Dickkopfs (Dkks) and Frizzledrelated proteins (FRPs). One of the long term goals of our laboratory is to understand how specificity is generated for the different signaling pathways. The following projects are currently being pursued in the laboratory. Analysis of Lrp5-deficient mice Recently, several laboratories have demonstrated that Lrp5 is required for the maintenance of normal bone density in humans. Consistent with the work of other laboratories, we have shown that Lrp5-deficient mice are viable and fertile but have decreased bone density and persistent vascularization of the lens. We have created Lrp5-deficient mice on several genetic Figure 1. Overview of the Wnt signaling pathway (Reprinted by permission from Nature Cell Biology 4(7): E172-E173, © (2002) Macmillan Publishers Ltd.) 56

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