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

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.

Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification

“…Our results also show that AZI overexpression leads to significantly higher levels of cyclin D1 and ODC whose stability are both regulated by antizyme 1 (Murakami et al, 1992;Newman et al, 2004). Overexpression of cyclin D1 has been reported to induce centrosome abnormalities, but it led to hyperamplification of centrosomes with equal numbers of daughter and mother centrioles (Nelsen et al, 2005). Hence it is unlikely that the antizyme 1/AZI system regulates centrosome homeostasis through cyclin D1.…”

Cortactin expression predicts poor survival in laryngeal carcinoma

“…Increased expression of cyclin D1 is detected at early stages of tumorigenesis and found prior to amplification (Izzo et al, 1998). Interestingly, cyclin D1 overexpression enhances cell division and results in genomic instability (Nelsen et al, 2005). On the other hand, cortactin overexpression might induce an increase in the invasive potential affecting later stages of cancer development (this study).…”

“…Gene by gene functional analyses have revealed that cyclin D1 (Opitz et al, 2001;Nelsen et al, 2005), FADD (Alappat et al, 2003;Chen et al, 2005) and cortactin (van Rossum et al, 2003;Luo et al, 2006) are potentially able to enhance cancer development. However, these studies do not account for the effect of multiple genes located within the 11q13.3 amplicon.…”

Cell cycle regulation and hepatocarcinogenesis

“…77 A potential explanation for the association between cyclin D1 and tumor aggressivity is suggested by experiments in which transient overexpression of cyclin D1 in mouse hepatocytes is associated with the development of chromosomal abnormalities including centrosome amplification, mitotic spindle abnormalities. 78 In contrast to the regulatory mechanisms responsible for Cyclin D1 induction in the partial hepatectomy model, increased expression of Cyclin D1 in HCCs is thought to be the result of gene amplification or chromosomal rearrangements. 77 These observations suggest that Cyclin D1 overexpression is likely to be a late aberration in HCCs that affects tumor growth rather than tumor initiation.…”