Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53-/- cells

Abstract

Aberrations in centrosome numbers have long been implicated in aneuploidy and tumorigenesis, but their origins are unknown. Here we have examined how overexpression of Aurora‐A kinase causes centrosome amplification in cultured cells. We show that excess Aurora‐A does not deregulate centrosome duplication but gives rise to extra centrosomes through defects in cell division and consequent tetraploidization. Over expression of other mitotic kinases (Polo‐like kinase 1 and Aurora‐B) also causes multinucleation and concomitant increases in centrosome numbers. Absence of a p53 checkpoint exacerbates this phenotype, providing a plausible explanation for the centrosome amplification typical of p53−/− cells. We propose that errors during cell division, combined with the inability to detect the resulting hyperploidy, constitute a major cause for numerical centrosome aberrations in tumors.

Cytokinesis arrest and multiple centrosomes in B cell chronic lymphocytic leukaemia

“…Our data also indicate that centrosome aberrations in malignant cells can arise via mitotic defects. The described cytokinesis failure leading to cells that harbour supernumerary centrosomes resembles the findings described for overexpression of Plk1, Evi1, Aurora A and Aurora B 41, 44…”

“…Previous studies have linked cytokinesis defects, multiple centrosomes and accumulation of cells in G0/1 to be a consequence of dysregulation of important players in cell cycle regulation 34. Centrosome amplification can be induced via deregulation of the centrosome duplication process in interphase 35, 36, 37, 38, 39, 40, 41, 42, 43 or through mitotic defects resulting in G0/1 cells with tetraploid cells 44. The latter can be experimentally induced by overexpression of Plk1, Aurora A and Aurora B 41, 44.…”

Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation

“…This observation indicates that overexpression of Aurora-A resulted in centrosome amplification. It was shown previously in cultured cells that overexpression of Aurora-A resulted in chromosome tetraploidization, which serves as a major route for centrosome amplification (Meraldi et al, 2002). To investigate this, we performed chromosome spread using mammary epithelial cells.…”

“…Aurora-A is localized at the centrosome during interphase, translocated to the mitotic spindle in early mitotic phase and degraded after metaphase transition. It has been demonstrated that activation of Aurora-A is required for mitotic entry, centrosome maturation and separation and G2 to M transition (Marumoto et al, 2002;Meraldi et al, 2002;Anand et al, 2003;Hirota et al, 2003;Giet et al, 2005). Overexpression of Aurora-A also results in defective spindle assembly checkpoint, allowing cells with abnormal chromosomal separation to enter anaphase, leading to aneuploidy (Zhou et al, 1998;Stenoien et al, 2003).…”

Function and regulation of Aurora/Ipl1p kinase family in cell division

“…Moreover, it has been shown that over-expression of Aurora-A in diploid human breast epithelial cells causes aberrant centrosome replication, as well as induction of aneuploidy, indicating that there are intrinsic links between aberrant regulation of Aurora-A activity and pathogeneses of aneuploidy and chromosomal instability [70,71]. Recently, Meraldi et al show that over-expression of Aurora-A gave rise to centrosome amplification and polyploid [72]. Interestingly, both phenotypes was enhanced in a p53-/-background, indicating that p53-dependent checkpoint may function at eliminating cells underwent aberrant cell division [73].…”