1. ¹Section of Hematology/Oncology, Rangos Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
2. ²Department of Molecular Genetics and Biochemistry, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
3. ³University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Correspondence: Dr EV Prochownik, Section of Hematology/Oncology, Children's Hospital of Pittsburgh, Rangos Research Center, Room 8125, 3460 Fifth Avenue, Pittsburgh, PA 15213, USA. E-mail: procev@chp.edu

Received 2 July 2007; Revised 8 August 2007; Accepted 10 August 2007; Published online 17 September 2007.

Abstract

GpIb, a subunit of the von Willebrand factor receptor, functions during blood clotting to promote platelet adhesion and activation. GpIb is widely expressed, is positively regulated by c-Myc and is essential for the promotion of c-Myc-mediated chromosomal instability. We now show that GpIb is also a classical oncoprotein in which its deregulated expression leads to transformation, reduced growth factor requirements, increased resistance to apoptosis, and, in primary cells, p53-dependent senescence. Finally, GpIb also promotes double-stranded DNA breaks, and induces profound nuclear dysmorphology, indicating that, in addition to its direct transforming function, it displays genotoxicity at several distinct levels. These findings identify novel functions for GpIb and pathways through which c-Myc mediates transformation and global genomic destabilization.