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c-Myc-mediated genomic instability proceeds via a megakaryocytic endomitosis pathway involving Gp1bα
- Li, Youjun, Lu, Jie, Prochownik, Edward V.
- Proceedings of the National Academy of Sciences of the United States of America 2007 v.104 no.9 pp. 3490-3495
- adhesion, aneuploidy, blood platelets, cell adhesion, chromosomes, endopolyploidy, evolution, gene expression regulation, gene overexpression, genes, neoplasms, oncogene proteins, tetraploidy
- Genomic instability (GI) is essential for the initiation and evolution of many cancers and often precedes frank neoplastic conversion. Although GI can occur at several levels, the most conspicuous examples involve gains or losses of entire chromosomes (aneuploidy), the antecedent of which may be whole genome duplication (tetraploidy). Through largely undefined mechanisms, the c-Myc oncoprotein and its downstream target, MTMC1, promote tetraploidy and other forms of GI. In myeloid cells, c-Myc and MTMC1 also regulate a common, small subset of c-Myc target genes including GP1Bα, which encodes a subunit of the von Willebrand's factor receptor complex that mediates platelet adhesion and aggregation. Gp1bα also participates in megakaryocyte endomitosis, a form of controlled and precise whole-genome amplification. In this article, we show that both c-Myc and MTMC1 strongly up-regulate Gp1bα concurrent with their promotion of tetraploidy. shRNA-mediated inhibition of Gp1bα prevents tetraploidy by both c-Myc and MTMC1, whereas Gp1bα overexpression alone is sufficient to induce tetraploidy in established and primary cells. Once acquired, tetraploidy persists in most cases examined. Our results indicate that chromosome-level GI, induced by c-Myc overexpression, proceeds by means of the sequential up-regulation of MTMC1 and Gp1bα and further suggest that the pathways leading to megakaryocytic endomitosis and c-Myc-induced tetraploidy are mechanistically linked by their reliance on Gp1bα.