Original Article
Oncogene (2008) 27, 1599–1609; doi:10.1038/sj.onc.1210794; published online 17 September 2007
Transformation, genomic instability and senescence mediated by platelet/megakaryocyte glycoprotein Ib
Y Li1, J Lu1, D Cohen1 and E V Prochownik1,2,3
- 1Section of Hematology/Oncology, Rangos Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
- 2Department of Molecular Genetics and Biochemistry, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- 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.
Keywords:
c-Myc, tetraploidy, aneuploidy, von Willebrand's factor
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