p53 protein accumulation in addition to the transactivation activity is required for p53-dependent cell cycle arrest after treatment of cells with camptothecin

In this studyw we characterize the connections between p53-dependent G1 cel l cycle arrest, transcriptional activation of the protein and the increase of its intracellular steady-state concentration, Several cell lines express ing wild-type p53 protein were treated with increasing concentrations of DN A-damaging drug camptothecin, Lower doses of the drug caused transcriptiona l activation of p53, but no accumulation of the protein was detected. Only after a certain threshold dose of camptothecin does the amount of the prote in rapidly increase and reach its plateau levels. The threshold dose was di fferent for different cell lines, but the general non-linear profile was si milar, Increase of p53 level was accompanied by additional transcriptional activation of some p53 target genes (i,e, waf1), but not the others (mdm2), We demonstrate here that transcriptional activation of p53 after the treat ment of camptothecin is not sufficient to cause p53-dependent G1 cell cycle arrest. The latter is observable only after the inrease of steady-state le vel of p53, Low drug concentrations, although accompanied by transcriptiona l activation of p53, do not cause either p53 protein accumulation nor cell cycle arrest at G1, We propose a model for p53 acting as a part of cellular sensor system detecting the severity of DNA damage.