p53-mediated cell death: relationship to cell cycle control.

Abstract

Ml clone S6 myeloid leukemic cells do not express detectable p53 protein. When stable transfected with a temperature-sensitive mutant of p53, these cells undergo rapid cell death upon induction of wild-type (wt) p53 activity at the permissive temperature. This process has features of apoptosis. In a number of other cell systems, wt p53 activation has been shown to induce a growth arrest. Yet, wt 53 fails to induce a measurable growth arrest in Ml cells, and cell cycle progression proceeds while viability is being lost. There exists, however, a relationship between the cell cycle and p53-mediated death, and cells in G, appear to be preferentially susceptible to the death-inducing activity of wt p53. In addition, p53-mediated Ml cell death can be inhibited by interleukin-6. The effect of the cytokine is specific to p53-mediated death, since apoptosis elicited by serum deprivation is refractory to interleukin-6. Our data imply that p53-mediated cell death is not dependent on the induction of a growth arrest but rather may result from mutually incompatible growthregulatory signals.The p53 phosphoprotein is the product of a tumor suppressor gene, whose inactivation may play a role in the development and progression of many types of cancer (reviewed in references 5, 26, 35, and 43). In most cases,

Enhancement of radiosensitivity by topoisomerase II inhibitor, amrubicin and amrubicinol, in human lung adenocarcinoma A549 cells and kinetics of apoptosis and necrosis induction

“…The induction of necrosis following radiotherapy also increased with time and there was a significant increase in the induction of necrosis after 4 h of exposure to AMROH followed by X-ray irradiation. The p53-mediated apoptosis has been thought to be cell cycle dependent (24,56). We have reported that a cell phase response of A549 cells with wtp53 to AMR or AMROH was not seen regardless of the agent concentrations (13).…”

“…When DNA is damaged, wild-type p53 protein is activated by a phosphorylation signaling pathway, after which it exhibits antitumor effects by inducing either apoptosis or G 1 arrest (17)(18)(19)(20)(21)(22). In several studies of cultured cells, it has also been found that cells with wild-type p53 are more radiosensitive than cells with mutant p53 (23)(24)(25)(26). The ras gene was one of the first oncogenes discovered and is known to be involved in cellular proliferation and differentiation (27)(28)(29).…”

Bcl-2 inhibits p53 nuclear import following DNA damage

“…Our ®ndings do not enable an assessment of the impact of enforced bcl-2 expression on the ability of wild-type p53 to mediate cell cycle arrest following DNA damage in that growth arrest was not observed in either irradiated control or LNCaP-bcl-2 cells. It has recently been demonstrated that the cell cycle arrest and apoptotic functions of wild-type p53 are distinct and separable and that the ability of p53 to mediate apoptosis is not dependent on preceding cell cycle arrest (Yonish-Rouach et al, 1993;Abrahamson et al, 1995;Lin and Benchimol, 1995;Little et al, 1995;Chen et al, 1996;Wang et al, 1996;Rowan et al, 1996). Furthermore, it has been shown that overexpression of wild-type p53 does not in all circumstances result in upregulation of p21 waf1/cip1 (Jordan et al, 1997) and that even though expression of p21 waf1/cip1 may be induced this does not invariably result in cell cycle arrest (Sheikh et al, 1996;Little et al, 1995).…”

Differential regulation of survivin by p53 contributes to cell cycle dependent apoptosis

“…Dual roles of these molecules such as c-Myc, p53, survivin and Bcl-2 provide a rational linkage between cell cycle and apoptosis [3,[6][7][8][9]. Among these factors, tumor suppressor p53 performs a pivotal role switching between cell cycle regulation and apoptosis induction [10,11].…”