Short term cyclin D1 overexpression induces centrosome amplification, mitotic spindle abnormalities, and aneuploidy.
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.
Nelsen
Christopher J
CJ
Division of Gastroenterology, Hennepin County Medical Center, Minneapolis, Minnesota 55415, USA.
Kuriyama
Ryoko
R
Hirsch
Betsy
B
Negron
Vivian C
VC
Lingle
Wilma L
WL
Goggin
Melissa M
MM
Stanley
Michael W
MW
Albrecht
Jeffrey H
JH
D000782:Aneuploidy; D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism*; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008941:Spindle Apparatus / Q000378:metabolism* / Q000648:ultrastructure
D019938:Cyclin D1