Carcinogenesis is a multistep process, comprising uncontrolled cell proliferation, invasion and metastasis. Malignant transformation is characterized by disruption of cytoskeletal organization and decreased adhesion. An integral component of cytoskeletal function, IQGAP1 is expressed at increased levels in a number of tumors and in highly metastatic cells. Moreover, IQGAP1 interacts functionally with several proteins implicated in carcinogenesis, including Cdc42, calmodulin, E-cadherin and beta-catenin. Therefore, the hypothesis to be evaluated in this proposal is that deregulation of the normal homeostatic interactions among IQGAP1 and its target proteins contributes to tumorigenesis.
Specific Aims : (1) To determine whether IQGAP1 promotes tumorigenesis, intracellular IQGAP1 concentrations and function will be manipulated, and cellular proliferation and transformation will be assessed in vitro and in vivo. (2) To characterize the effects of IQGAP1 on cell motility and invasion, these parameters will be measured with breast epithelial cells in which IQGAP 1 concentrations and function have been modified. In addition, the molecular mechanisms(s) by which IQGAP1 promotes cell motility and invasion will be examined by altering the function of selected IQGAP1 target proteins in cells in which IQGAP1 concentrations are increased or decreased. (3) To determine whether Ca2+/calmodulin modulates the effects of IQGAP1 on tumorigenesis, calmodulin function and its binding to IQGAP1 will be disrupted. The consequences of these manipulations on cellular proliferation, motility and invasion will be examined. These studies should provide insight into breast epithelial cell biology and the regulation of cytoskeletal architecture and cell motility. The long-term goal of this program is the development of novel and specifically targeted pharmacologic agents for the treatment of carcinoma.
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