Deregulation of CMYC is a hallmark of many human cancers. As a general bHLH-ZIP transcription factor, the c-Myc oncoprotein directly regulates the expression of > 1500 genes controlled by RNA polymerases I, II and III. This represents a formidable challenge to determining which are the most critical for transformation. Previous work from our laboratory has indicated that MT-MC1, a direct c-Myc target gene, mimics many c-Myc phenotypes. More recently, genome-wide microarray experiments indicate that MT-MC1 itself regulates fewer than 50 downstream target genes, many of which, if not all, are also c-Myc targets. These observations suggest that this small, overlapping subset of target genes plays a particularly important role in c-Myc-mediated transformation. This is supported by the finding that nearly half of MT-MC1-regulated genes have been previously implicated in cancer.

GpIba, a subunit of the von Willebrand factor receptor, functions during blood clotting to promote platelet adhesion and activation. GpIba 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 GpIba 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, GpIba 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 GpIba and pathways through which c-Myc mediates transformation and global genomic destabilization.

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