p53 checkpoint-defective cells are sensitive to X rays, but not hypoxia

X-ray-induced damage leads to cell-cycle "checkpoint" arrest by p53-depende nt induction of the cyclin-dependent kinase inhibitor p21 (Waf1/Cip1/Sdi1). Human tumor cells that lack this response fail to arrest after exposure to DNA-damaging agents, undergo multiple rounds of endoreduplicative DNA synt hesis, and eventually commit to an apoptotic cell death. Since low oxygen t ension can also induce p53 protein accumulation, and can lead to cell-cycle arrest or apoptosis, we examined the expression of p21 in tumor cells unde r normoxic and hypoxic conditions. In a survey of cells, mRNA for the p21 g ene was induced two- to threefold in response to hypoxia in a seemingly p53 -independent manner. We therefore examined genetically matched cells that d iffer in their p21 and p53 status for response to ionizing radiation and hy poxia. We found that both pal-deficient and p53-deficient cells exhibit an increase in chromosome instability, an increased level of apoptosis, and a failure to arrest after exposure to ionizing radiation. However, cells that lack either p21 or p53 exhibit no increase in chromosome instability or el evated apoptosis and still arrest in response to hypoxia. Thus, the mechani sm responsible for the differential response to either hypoxia or X rays pr esumably lies in the control of cell-cycle progression in response to stres s and its dependence on p21. Since the loss of a DNA-damage-dependent check point does not sensitize cells to killing by stresses that elicit a DNA-dam age-independent checkpoint, targeting the function of p21 pharmacologically will not kill tumor cells in situ in the absence of a DNA damage signal. ( C) 2000 Academic Press.