p53-Independent Apoptosis and p53-Dependent Block of DNA Rereplication Following Mitotic Spindle Inhibition in Human Cells

Switch from p53 to MDM2 as differentiating human keratinocytes lose their proliferative potential and increase in cellular size

“…Our observations strongly support this model when considered alongside other lines of evidence: (a) the deregulation of the p53/p21 Cip1 pathway has been found to produce a defective cell cycle and polyploidy in leukemic cells and E1A/ras transformed embryo ®broblasts (Peled et al, 1996;Bulavin et al, 1999); (b) loss of p53 allows endoreplication after mitotic spindle inhibition in a variety of systems, whereas its presence is able to suppress it (Minn et al, 1996;Di Leonardo et al, 1997;Notterman et al, 1998;Casenghi et al, 1999); (c) MDM2 expression in transgenic mammary gland produced enlarged polyploid cells (Lundgren et al, 1997;Reinke et al, 1999); (d) overexpression of p53 target p21 Cip1 has been reported to block cell cycle in G2/M and cause endoreplication and polyploidy when Rb was not functional in a variety of mouse and human cells, including a human epidermoid carcinoma (Niculescu et al, 1998). Consistently, we and others have found that p21 Cip1 is upregulated and Rb down-regulated during keratinocyte di erentiation (Figure 1c; Harvat et al, 1998;Hauser et al, 1997;unpublished results) and MDM2 has the capacity to inhibit Rb (Xiao et al, 1995).…”

p53 Localization at Centrosomes during Mitosis and Postmitotic Checkpoint Are ATM-dependent and Require Serine 15 Phosphorylation

“…However, microtubule-depolymerizing agents disrupt the p53 centrosomal association, provoking p53 stabilization and arrest in the G1 phase of the following cell cycle (Ciciarello et al, 2001). Although the latter finding strongly supports a previously identified role for p53 in the so-called postmitotic checkpoint (for details, see Minn et al, 1996;Lanni and Jacks, 1998;Casenghi et al, 1999), the biological significance of p53 localization at the centrosomes in mitosis still remains to be elucidated. It may be speculated that microtubule-driven transport to centrosomes prevents p53 from being activated "by default" in mitosis and that the failure of p53 association with centrosomes constitutes the trigger for postmitotic checkpoint activation.…”

G1 and G2 cell-cycle arrest following microtubule depolymerization in human breast cancer cells

“…The failure of type B cells to accumulate in mitosis when followed for as long as 72 hours after treatment with 1 µM nocodazole or 100 nM vincristine (Figure 1 (Figure 3, b, c, and g). Although microtubule-disrupting agents have been observed to induce accumulation in a tetraploid G 1 -like state following mitotic delay and abnormal mitotic exit (11,(14)(15)(16)(17)(18)(19)(20), to our knowledge this is the first report of premitotic G 1 and G 2 arrest induced by these agents.…”

“…After prolonged treatment with microtubule-disrupting agents, cells exit mitosis without undergoing cytokinesis. These cells then enter an abnormal, tetraploid G 1 -like phase (10)(11)(12)(13) in which they are susceptible to activation of a "microtubulesensitive" G 1 checkpoint (11,14,15) that results in p53-mediated upregulation of the cyclin-dependent kinase (Cdk) inhibitor p21 Waf1/Cip1 (p21) (16)(17)(18)(19)(20). p21 in turn inhibits the activity of Cdk2-and Cdk4-cyclin complexes, thereby arresting the cells in a tetraploid G 1 state (reviewed in ref.…”