Coordination between cell cycle progression and cell fate decision by the p53 and E2F1 pathways in response to DNA damage.
After DNA damage, cells must decide between different fates including growth arrest, DNA repair, and apoptosis. Both p53 and E2F1 are transcription factors involved in the decision process. However, the mechanism for cross-talk between the p53 and E2F1 pathways still remains unclear. Here, we proposed a four-module kinetic model of the decision process and explored the interplay between these two pathways in response to ionizing radiation via computer simulation. In our model the levels of p53 and E2F1 separately exhibit pulsatile and switching behaviors. Upon DNA damage, p53 is first activated, whereas E2F1 is inactivated, leading to cell cycle arrest in the G(1) phase. We found that the ultimate decision between cell life and death is determined by the number of p53 pulses depending on the extent of DNA damage. For repairable DNA damage, the cell can survive and reenter the S phase because of the activation of E2F1 and inactivation of p53. For irreparable DNA damage, growth arrest is overcome by growth factors, and activated p53 and E2F1 cooperate to initiate apoptosis. We showed that E2F1 promotes apoptosis by up-regulating the proapoptotic cofactors of p53 and procaspases. It was also revealed that deregulated E2F1 by oncogene activation can make cells sensitive to DNA damage even in low serum medium. Our model consistently recapitulates the experimental observations of the intricate relationship between p53 and E2F1 in the DNA damage response. This work underscores the significance of E2F1 in p53-mediated cell fate decision and may provide clues to cancer therapy.
Zhang
Xiao-Peng
XP
National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University, Nanjing 210093, China.
Liu
Feng
F
Wang
Wei
W
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004249:DNA Damage / Q000502:physiology*; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D016196:S Phase / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53