Multiple centrosomes arise from tetraploidy checkpoint failure and mitotic centrosome clusters in p53 and RB pocket protein-compromised cells

Abstract

A high degree of aneuploidy characterizes the majority of human tumors. Aneuploid status can arise through mitotic or cleavage failure coupled with failure of tetraploid G 1 checkpoint control, or through deregulation of centrosome number, thus altering the number of mitotic spindle poles. p53 and the RB pocket proteins are important to the control of G 1 progression, and p53 has previously been suggested as important to the control of centrosome duplication. We demonstrate here that neither suppression of p53 nor of the RB pocket protein family directly generates altered centrosome numbers in any of several mammalian primary cell lines. Instead, amplification of centrosome number occurs in two steps. The first step is failure to arrest at a G 1 tetraploidy checkpoint after failure to segregate the genome in mitosis, and the second step is clustering of centrosomes at a single spindle pole in subsequent tetraploid or aneuploid mitosis. The trigger for these events is mitotic or cleavage failure that is independent of p53 or RB status. Finally, we find that mouse embryo fibroblasts spontaneously enter tetraploid G 1, explaining the previous demonstration of centrosome amplification by p53 abrogation alone in these cells.aneuploidy ͉ G1 phase ͉ pRB

Cyclin G2 is a centrosome-associated nucleocytoplasmic shuttling protein that influences microtubule stability and induces a p53-dependent cell cycle arrest

“…Due to the robust arrest responses induced by cytokinetic defects, it has been postulated that this response requires p53 [74,98,101,102]. In support of our hypothesis, we determined that the G 1 -phase cell cycle arrest induced by ectopic cyclin G2 expression is linked to its centrosomal targeting region and is p53-dependent.…”

Genotoxic stress leads to centrosome amplification in breast cancer cell lines that have an inactive G1/S cell cycle checkpoint

“…Several studies suggest that deregulation of the centrosome cycle may lead to the development of chromosomal instability through the formation of multipolar mitotic spindles and unequal chromosome segregation (Lingle and Salisbury, 1999;Goepfert et al, 2002;Kramer et al, 2002;Lingle et al, 2002;Duensing and Munger, 2003;Pihan et al, 2003). The tumor suppressor gene p53, mutated in more than 50% of human cancers (Lane and Benchimol, 1990;Levine et al, 1991), plays an important role in the maintenance of centrosome homeostasis since loss of p53 function can lead to centrosome defects (Fukasawa et al, 1996;Borel et al, 2002;Tarapore and Fukasawa, 2002). However, since p53-null mice develop normally and have normal centrosomes in most of their cells, the development of centrosome amplification in this model may result only after failure of p53 function following genotoxic stress.…”

Centrosome aberrations in chronic myeloid leukemia correlate with stage of disease and chromosomal instability

“…In addition to other unknown mechanisms, the effect may be brought about by mutations or an altered activity in the p53 tumor suppressor protein that has been demonstrated to be associated with centrosomes during mitosis and to be essential for centrosome duplication control. 40 Thus, centrosome alterations induced by BCR-ABL might function as an additional 'amplifier' of a genetically unstable phenotype and contribute to the expansion of cell clones with increasingly malignant characteristics. 2 In conclusion, our results indicate that centrosome defects are an early detectable feature in CML.…”