Abstract
In normal cells, cyclin D1 is induced by growth factors and promotes progression through the G(1) phase of the cell cycle. Cyclin D1 is also an oncogene that is thought to act primarily by bypassing the requirement for mitogens during the G(1) phase. Studies of clinical tumors have found that cyclin D1 overexpression is associated with chromosome abnormalities, although a causal effect has not been established in experimental systems. In this study, we found that transient expression of cyclin D1 in normal hepatocytes in vivo triggered dysplastic mitoses, accumulation of supernumerary centrosomes, abnormalities of the mitotic spindle, and marked chromosome changes within several days. This was associated with up-regulation of checkpoint genes p53 and p21 as well as hepatocyte apoptosis in the liver. Transient transfection of cyclin D1 also induced centrosome and mitotic spindle abnormalities in breast epithelial cells, suggesting that this may be a generalized effect. These results indicate that cyclin D1 can induce deregulation of the mitotic apparatus and aneuploidy, effects that could contribute to the role of this oncogene in malignancy.
Highlights
In normal cells, cyclin D1 is induced by growth factors and promotes progression through the G1 phase of the cell cycle
We have found that transient transfection of hepatocytes in vivo with a recombinant adenovirus expressing human cyclin D1 (ADV-D1) is sufficient to trigger hepatocyte replication and liver growth under conditions where these cells are normally quiescent (20 –22)
Current models suggest that overexpression of cyclin D1 alone is not sufficient to account for carcinogenesis; additional genetic changes are required in order for cells to acquire a malignant phenotype [42]
Summary
Cyclin D1 is induced by growth factors and promotes progression through the G1 phase of the cell cycle. We found that transient expression of cyclin D1 in normal hepatocytes in vivo triggered dysplastic mitoses, accumulation of supernumerary centrosomes, abnormalities of the mitotic spindle, and marked chromosome changes within several days. Transient transfection of cyclin D1 induced centrosome and mitotic spindle abnormalities in breast epithelial cells, suggesting that this may be a generalized effect.
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