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Polyploidization is observed in all mammalian species and is a characteristic feature of hepatocytes, but its molecular mechanism and biological significance are unknown. Hepatocyte polyploidization in rodents occurs through incomplete cytokinesis, starts after weaning and increases with age. Here, we show in mice that atypical E2F8 is induced after weaning and required for hepatocyte binucleation and polyploidization. A deficiency in E2f8 led to an increase in the expression level of E2F target genes promoting cytokinesis and thereby preventing polyploidization. In contrast, loss of E2f1 enhanced polyploidization and suppressed the polyploidization defect of hepatocytes deficient for atypical E2Fs. In addition, E2F8 and E2F1 were found on the same subset of target promoters. Contrary to the long-standing hypothesis that polyploidization indicates terminal differentiation and senescence, we show that prevention of polyploidization through inactivation of atypical E2Fs has, surprisingly, no impact on liver differentiation, zonation, metabolism and regeneration. Together, these results identify E2F8 as a repressor and E2F1 as an activator of a transcriptional network controlling polyploidization in mammalian cells.

Amplification of region 17p11.2 approximately p12 has been found in 13%-29% of high-grade osteosarcomas, suggesting the presence of an oncogene or oncogenes that may contribute to their development. To determine the location of these putative oncogenes, we established 17p11.2 approximately p12 amplification profiles by semiquantitative PCR, using 15 microsatellite markers and seven candidate genes in 19 high-grade osteosarcomas. Most of the tumors displayed complex amplification profiles, with frequent involvement of marker D17S2041 in 17p12 and TOP3A in 17p11.2 and, in some cases, very high-level amplification of PMP22 and MAPK7 in 17p11.2. Our findings suggest that multiple amplification targets, including PMP22, TOP3A, and MAPK7 or genes close to these candidate oncogenes, may be present in 17p11.2 approximately p12 and thus contribute to osteosarcoma tumorigenesis.