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[Relationships between p53 induction, cell cycle arrest and survival of normal human fibroblasts following DNA
J Ceraline1, G Deplanque, B Duclos
1Laboratoire d'oncologie moléculaire, Hôpitaux universitaires de Strasbourg, France.
Abstract:
It is now well established that in response to genotoxic stresses mammalian cells show an increased p53 protein levels and undergo cell cycle arrest at G1/S and G2/M checkpoints. But, the consequences of these cell cycle arrests on cell survival are not yet elucidated. In this study, we have analysed the relationships between p53 protein induction, 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 G2/M arrest arose at the same time following exposure to DNA damaging agents, suggesting that p53 is responsible for the G2/M block. However, following inhibition of p53 induction by an antisense oligonucleotide, this G2/M arrest is even more important and correlates with an enhanced 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 doses. We show that: 1) there appears to be a threshold in the cellular response to genotoxic agents, below which neither p53 induction, nor cell cycle arrest, nor cell survival alteration occur and beyond which p53 induction is accompanied by cell cycle arrest and decreased cell survival; 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 G2/M arrest, this latter is independent of p53; 3) p53 inhibition enhances NHFs' sensitivity to DNA damaging agents, the extent of the G2/M arrest correlating with decreased cell survival. Finally, the lack of obligatory correlation between p53 inactivation, apoptosis and radio- or chemoresistance is discussed.
Insights
Genotoxic stress increases p53 protein and cell cycle arrest, but this arrest, independent of p53, enhances cell sensitivity to DNA damage and impacts survival.
Area of Science:
- Cellular biology
- Molecular genetics
- DNA damage response
Context:
- Mammalian cells activate p53 and cell cycle arrest in response to genotoxic stress.
- The impact of these cell cycle arrests on cell survival remains unclear.
- This study investigates the interplay between p53, cell cycle arrest, and survival in human fibroblasts exposed to genotoxic agents.
Purpose:
- To elucidate the relationship between p53 induction, cell cycle arrest, and cell survival following genotoxic stress.
- To determine the role of p53 in G2/M cell cycle arrest.
- To assess the impact of p53 inhibition on cellular sensitivity to DNA damaging agents.
Summary:
- A threshold exists for genotoxic agent response; below it, no significant cellular changes occur, while above it, p53 induction correlates with cell cycle arrest and reduced survival.
- G2/M arrest occurs temporally with p53 induction but is independent of p53.
- Inhibition of p53 amplifies G2/M arrest and increases sensitivity to DNA damaging agents, indicating p53's role in cell survival modulation.
Impact:
- Findings challenge the direct role of p53 in G2/M arrest, suggesting it modulates rather than dictates the arrest.
- Highlights the complex relationship between DNA damage response pathways and cell fate decisions.
- Provides insights into potential therapeutic strategies targeting cell survival mechanisms in cancer treatment.