PIs: Edward V. Prochownik

Co-PIs: Eric Lagasse, William Saunders, and Youjun Li

Title: Function of a Glycoprotein Ibα, a Subunit of the Von Willebrand’s Factor Receptor as a Transforming Oncoprotein

Description: De-regulation of the CMYC gene and/or its encoded protein, c-Myc, are among the most common molecular abnormalities in human cancers. c-Myc is a particularly notorious oncoprotein because, in addition to being acutely transforming, it can also mediate genomic instability (GI) at several levels, which contributes to ongoing mutational changes and tumor cell evolution. A major focus of our laboratory has been the identification of transcriptional targets for c-Myc, which normally functions as a general transcription factor. Many c-Myc targets have been identified but only a small number have been shown actually to recapitulate the transforming properties of c-Myc itself. Recently, we have identified a totally unexpected down-stream target of c-Myc, GPIBα, whose encoded proteinGpIbα functions as a subunit of the von Willebrand’s factor receptor (VWFR), previously believed to be expressed only on platelets and megakaryocytes. In its traditional role, VWFR interacts with von Willebrand’s factor expressed by the vascular sub-endothelium and thus serves to immobilize platelets and allow their aggregation and activation during the initial stages of blood clot formation. Unexpectedly, we have found that GpIbα is necessary for c-Myc to promote GI and, by itself, is sufficient both for transformation and GI. In a large panel of normal and tumor cell lines, we have found that GpIbα is expressed at highest levels in the latter cells and in direct proportion to c-Myc. Now, in collaboration with Dr. Eric Lagasse (McGowan Institute for Regenerative Medicine) and Dr. William Saunders (University of Pittsburgh Department of Biological Sciences), we propose to explore further the mechanism(s) by which GpIbα promotes GI and cellular transformation and to delineate GpIbα’s role in in vivo tumorigenesis. Thus, in Specific Aim 1, we will define the mechanisms by which GpIbα over-expression leads to GI and transformation (Prochownik). In Specific Aim 2, we will assess the role of GpIbα in promoting tumorigenesis of established cancer cell lines (Prochownik). In Specific Aim 3, we will develop an in vivo model of GpIbα-mediated GI and transformation (Lagasse). Finally, in Specific Aim 4, we will evaluate in detail the nature of GpIbα-mediated GI (Saunders). Together, these studies will provide new insights into a previously unrecognized and unexpected oncoprotein, namely GpIbα, and will define the mechanisms by which this newly described function differs so dramatically from its traditional role in megakaryocytes and platelets.

Source: Children’s Hospital of Pittsburgh

Term: 7/1/08-6/30/09

Amount: $62,575