Characterization of the p53-Dependent Postmitotic Checkpoint following Spindle Disruption

Abstract

The p53 tumor suppressor gene product is known to act as part of a cell cycle checkpoint in G 1 following DNA damage. In order to investigate a proposed novel role for p53 as a checkpoint at mitosis following disruption of the mitotic spindle, we have used time-lapse videomicroscopy to show that both p53 ؊/؊ fibroblasts fail to arrest in response to nocodazole treatment and become polyploid. Moreover, p21 is required to a similar extent to maintain cell cycle arrest after either nocodazole treatment or irradiation. Thus, the p53-dependent checkpoint following spindle disruption functionally overlaps with the p53-dependent checkpoint following DNA damage.

Effects of hTERT on metal ion-induced genomic instability

“…Vanadium unlike chromium is known to inhibit microtubule assembly and induce tubulin depolymerization (Ramirez et al, 1997). Lanni and Jacks (1998) showed that adaption to another microtubule destabilizing drug (nocodazole) caused a p53-dependent G1 arrest. It is therefore possible that abnormal p53 signalling in hTERT þ cells was partly responsible for the tetraploidy caused by V (V).…”

Deregulation of Cdk2 causes Bim-mediated apoptosis in p53-deficient tumors following actin damage

“…The changes in PTX-2-treated p53-positive cells closely resemble those in normal cells treated with spindle inhibitors, which enter into tetraploid G 1 state (Lanni and Jacks, 1998). Cyclins D and E were increased, but cyclins A and B were decreased following PTX-2 treatment (Figure 2a), implying that those cells arrested at G 1 checkpoint.…”

“…After a delay period, cells eventually escape from this block (a process termed 'mitotic slippage'), and exit mitosis without a proper segregation of sister chromatids and cytokinesis (Jordan et al, 1991(Jordan et al, , 1996Torres and Horwitz, 1998). Therefore, spindle-damaged cells arrests at G 1 -like state with an intact nucleus containing 4N DNA, but without ever completing mitosis (Minn et al, 1996;Lanni and Jacks, 1998). This is recently termed as tetraploid G 1 state.…”

“…Cells lacking wild-type p53 are still able to arrest transiently at mitosis, underscoring that the delay in mitosis is p53-independent (Minn et al, 1996;Lanni and Jacks, 1998). However, the p53-deficient cells are not prevented from re-entering the cell cycle and can reduplicate their DNA unchecked, leading to polyploidy and subsequent genomic instability (Di Leonardo et al, 1997;Khan and Wahl, 1998;Lanni and Jacks, 1998).…”

“…However, the p53-deficient cells are not prevented from re-entering the cell cycle and can reduplicate their DNA unchecked, leading to polyploidy and subsequent genomic instability (Di Leonardo et al, 1997;Khan and Wahl, 1998;Lanni and Jacks, 1998). In addition to microtubule inhibitors, dihydrocytochalasin B (DCB), which induces cleavage failure by depolymerizing actin filaments, also lead to tetraploid G 1 arrest (Andreassen et al, 2001).…”