Crosstalk of the mitotic spindle assembly checkpoint with p53 to prevent polyploidy

Abstract

Treatment of cells with microtubule inhibitors results in activation of the mitotic spindle assembly checkpoint, leading to mitotic arrest before anaphase. Upon prolonged treatment, however, cells can adapt and exit mitosis aberrantly, resulting in the occurrence of tetraploid cells in G1. Those cells subsequently arrest in postmitotic G1 due to the activation of a p53-dependent G1 checkpoint. Failure of the G1 checkpoint leads to endoreduplication and further polyploidization. Using HCT116 and isogenic p53-deficient or spindle checkpoint compromised derivatives, we show here that not only p53 but also a functional spindle assembly checkpoint is required for postmitotic G1 checkpoint function. During transient mitotic arrest, p53 stabilization and activation is triggered by a pathway independent of ATM/ATR, Chk1 and Chk2. We further show that a prolonged spindle checkpoint-mediated mitotic arrest is required for proper postmitotic G1 checkpoint function. In addition, we demonstrate that polyploid cells are inhibited to re-enter mitosis by an additional checkpoint acting in G2. Thus, during a normal cell cycle, polyploidization and subsequent aneuploidization is prevented by the function of the mitotic spindle checkpoint, a p53-dependent G1 checkpoint and an additional G2 checkpoint.

Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol

“…Under these conditions, the multinuclei contained a tetraploid DNA content as demonstrated by FACS analyses (Figure 2f). Furthermore, the premature exit from mitosis in spindle checkpoint deficient cells resulted in a similar high rate of endoreduplication in MAD1-kd and HCT-MAD2 þ /À cells (data not shown; Vogel et al, 2004a). Taken together, partial downregulation of either MAD1 or MAD2 results in a very similar functional inactivation of the spindle checkpoint.…”

Curcumin derivatives: Molecular basis of their anti-cancer activity

“…Mitotic slippage leads to the accumulation of postmitotic G1 cells, which are subsequently arrested in their cell cycle progression by activating a p53-dependent G1 checkpoint [37,38,39].…”

Mitotic Arrest and Cell Fate: Why and How Mitotic Inhibition of Transcription Drives Mutually Exclusive Events

“…Thus, although mitotic events (apoptosis and slippage) are p53-independent because the accumulated p53 cannot trans-activate during mitosis anyway, both post-mitotic apoptosis and G 1 arrest are p53-dependent, relying on Bax and p21, respectively. 6,60,[68][69][70][71][72] In summary, apoptosis-I and -II are drastically different: the former results from inhibition of transcription and the latter results from transcriptional rebound.…”

“…41,60,78 Perhaps, phosporylation of p53 causes its stabilization, during a transient mitotic arrest. 60 Thus, even before depletion of Mdm-2, phosphorylation of p53 may prevent p53 degradation. In addition, since most proteins are phosphorylated during mitosis, COP1 and Mdm-2 might be phosphorylated too.…”

“…57 Like inhibitors of transcription, microtubule active drugs (paclitaxel, vincristine, nocodazole), which cause mitotic inhibition of transcription, cause p53 accumulation. 10,41,[58][59][60][61] During mitotic arrest, p53 cannot induce its targets, because transcription is impossible. It was noticed that levels of p21 are decreased specifically during mitotic arrest despite an elevated levels of p53.…”