RELATIONSHIPS BETWEEN P53 INDUCTION, CELL -CYCLE ARREST AND SURVIVAL OF NORMAL HUMAN FIBROBLASTS FOLLOWING DNA-DAMAGE

It is now well established that in response to genotoxic stresses mamm alian cells show an increased p53 protein levels and undergo cell cycl e arrest at G(1)/S and G(2)/M checkpoints. But, the consequences of th ese cell cycle arrests on cell survival are not yet elucidated. In thi s study, we have analysed the relationships between p53 protein induct ion, cell cycle arrest and cell survival following exposure of normal human fibroblasts (NHFs) to various genotoxic agents such as cisplatin , UV radiation and gamma radiation. p53 protein accumulation and G(2)/ M arrest arised at the same time following exposure to DNA damaging ag ents, suggesting that p53 is responsible for the G(2)/M block. However , following inhibition of p53 induction by an antisense oligonucleotid e, this G(2)/M arrest is even more important and correlates with an en hanced sensitivity of NHFs to UV radiation. In addition, there appears to be a threshold in the response of NHFs to DNA damaging agents, p53 induction and cell cycle arrest being observed only with lethal UV do ses. We show that: 1) there appears to be a threshold in the cellular response to genotoxic agents, below which neither p53 induction, nor c ell cycle arrest, nor cell survival alteration occur and beyond which p53 induction is accompanied by cell cycle arrest and decreased cell s urvival; 2) although there is a tight temporal relationship, the onset of which depends of the DNA damaging agent used, between the start of p53 induction and the occurrence of G(2)/M arrest, this latter is ind ependent of p53; 3) p53 inhibition enhances NHFs' sensitivity to DNA d amaging agents, the extent of the G(2)/M arrest correlating with decre ased cell survival. Finally, the lack of obligatory correlation betwee n p53 inactivation, apoptosis and radio- or chemoresistance is discuss ed.