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J. Biol. Chem., Vol. 280, Issue 1, 768-776, January 7, 2005

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Short Term Cyclin D1 Overexpression Induces Centrosome Amplification, Mitotic Spindle Abnormalities, and Aneuploidy^*

Christopher J. Nelsen, Ryoko Kuriyama¶||, Betsy Hirsch||**, Vivian C. Negron, Wilma L. Lingle, Melissa M. Goggin, Michael W. Stanley, and Jeffrey H. Albrecht||¶¶

From the Division of Gastroenterology, Hennepin County Medical Center, Minneapolis, Minnesota 55415, the Minneapolis Medical Research Foundation, Minneapolis, Minnesota 55404, the ^¶Department of Genetics, Cell Biology, and Development, University of Minnesota, the ^||University of Minnesota Cancer Center, the ^**Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, the Division of Experimental Pathology, Tumor Biology Program, Mayo Clinic, Rochester, Minnesota 55905, and the Department of Pathology, Hennepin County Medical Center, Minneapolis, Minnesota 55415

In normal cells, cyclin D1 is induced by growth factors and promotes progression through the G₁ 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 G₁ 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.

Received for publication, June 24, 2004 , and in revised form, October 26, 2004.

^* This work was supported by National Institutes of Health Grant DK54921 and a special grant from the University of Minnesota Cancer Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶¶ To whom correspondence should be addressed: Division of Gastroenterology (G5), Hennepin County Medical Center, 701 Park Ave., Minneapolis, MN 55415. Tel.: 612-873-8582; Fax: 612-904-4366; E-mail: albre010{at}tc.umn.edu.

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