Brent R. Blackman, PhD
Role of cellular factors in regulating endothelial cell organization in normal and cancer cell vaculature
The most active research project in the Bloom laboratory is focused on IQGAP1, a key regulatory protein for cellular motility and adhesion, and the product of a potential oncogene. The lab has been taking a multi-dimensional approach to study IQGAP1 since first identifying it as a novel actin-filament binding protein. This activity of IQGAP1 was recently found by the lab to underly Its potent ability to stimulate branched actin filament assembly. This dynamic process powers the lammelipodial protrusion that enables normal cells to move and change shape, and tumor cells to invade tissues. The functions, mechanisms of action, and regulation of IQGAP1 are being studied by in vitro reconstitution of actin assembly, and in cultured cells. Efforts to date indicate that IQGAP1 becomes activated for stimulating actin assembly by binding to the cytoplasmic tails l of multiple growth factor receptors, after the receptors engage their cognate ligands, including VEGF, FGF and PDGF.
The lab has also been collaborating with two other UVA Cancer Center members, Drs. Stephen Powell and Henry Frierson, on a possible role for IQGAP1 in stomach cancer. The motivation for this study was knowledge that the human IQGAP1 gene is located within a chromosome 15 locus that is a genetic hotspot for diffuse gastric carcinoma, and that IQGAP1 is abundantly expressed in gastric epithelium. Sequencing of IQGAP1 genomic DNA derived from a collection of diffuse and intestinal type human gastric carcinomas has demonstrated a rare coding mutation (M1231I) and several high allelic fequency (>20%) intronic expansions specifically in diffuse type carcinoma. To test the hypothesis that the coding mutation is oncogenic, wild type and M1231I forms of human IQGAP1 are now being expressed as transgenes in IQGAP1 knockout mice. Additional studies that are planned or underway include determining how the M1231I mutation alters the biochemical properties of IQGAP1, whether the intronic expansions lead to altered IQGAP1 isoform expression, and whether IQGAP1 expression is altered in diffuse gastric carcinoma. Currently being explored also is the possibility that IQGAP1 mutations can serve as diagnostic markers for diffuse gastric carcinoma.