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 G1 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. 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 G1 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. IntroductionThe tumor suppressor p53 has a crucial role in preventing tumorigenesis (1Meek D.W. Nat. Rev. Cancer. 2009; 9: 714-723Crossref PubMed Scopus (487) Google Scholar). Upon various stresses, p53 is stabilized and activated to function primarily as a transcription factor, regulating the expression of a large number of genes involved in cell cycle arrest, DNA repair, or apoptosis (2Murray-Zmijewski F. Slee E.A. Lu X. Nat. Rev. Mol. Cell Biol. 2008; 9: 702-712Crossref PubMed Scopus (331) Google Scholar). Thus, p53 is at the hub of numerous signaling pathways triggered by various stresses. Previously, it was proposed that cell fate after DNA damage is governed by p53 levels, i.e. a low level of p53 leads to transient growth arrest and cell survival, whereas a high level promotes irreversible apoptosis (3Vousden K.H. Lane D.P. Nat. Rev. Mol. Cell Biol. 2007; 8: 275-283Crossref PubMed Scopus (1707) Google Scholar). Recently, it has been reported that p53 levels can exhibit oscillations in response to DNA damage induced by ionizing radiation (IR) (4Lev Bar-Or R. Maya R. Segel L.A. Alon U. Levine A.J. Oren M. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 11250-11255Crossref PubMed Scopus (479) Google Scholar, 5Lahav G. Rosenfeld N. Sigal A. Geva-Zatorsky N. Levine A.J. Elowitz M.B. Alon U. Nat. Genet. 2004; 36: 147-150Crossref PubMed Scopus (804) Google Scholar). Whereas damped oscillations of p53 levels were observed at the population level (4Lev Bar-Or R. Maya R. Segel L.A. Alon U. Levine A.J. Oren M. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 11250-11255Crossref PubMed Scopus (479) Google Scholar), a series of undamped pulses was observed at the single-cell level (5Lahav G. Rosenfeld N. Sigal A. Geva-Zatorsky N. Levine A.J. Elowitz M.B. Alon U. Nat. Genet. 2004; 36: 147-150Crossref PubMed Scopus (804) Google Scholar). In such a digital mode, it is the number of p53 pulses rather than their amplitudes and duration that is related to the extent of DNA damage and determines cell fate (5Lahav G. Rosenfeld N. Sigal A. Geva-Zatorsky N. Levine A.J. Elowitz M.B. Alon U. Nat. Genet. 2004; 36: 147-150Crossref PubMed Scopus (804) Google Scholar). p53 pulses can be generated by negative feedback loops with time delay (6Ma L. Wagner J. Rice J.J. Hu W. Levine A.J. Stolovitzky G.A. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 14266-14271Crossref PubMed Scopus (291) Google Scholar, 7Geva-Zatorsky N. Rosenfeld N. Itzkovitz S. Milo R. Sigal A. Dekel E. Yarnitzky G. Alon U. Mol. Biol. PubMed Scopus Google Scholar, E. A. G. Mol. 2008; PubMed Scopus Google or and negative feedback loops A. J.J. Cell 2005; PubMed Scopus Google Scholar, J.J. Cell 2007; PubMed Scopus Google cells p53 pulses to various different is explored the of p53 pulses in response to DNA damage. and J.J. Cell 2007; PubMed Scopus Google p53 to and showed that p53 pulses the decision between cell cycle and apoptosis. We model of the p53 signaling to the process the of DNA damage to the of cell that two of p53 in cell fate decision F. W. Proc. Natl. Acad. Sci. U.S.A. 2009; PubMed Scopus Google Scholar). E. A. G. Nat. Rev. Cancer. 2009; 9: PubMed Scopus Google proposed that p53 pulses can for a of expression of that the pulsatile response of p53 may a and mechanism by can be the different by p53 are with p53 is to cell fate cross-talk between p53 and transcription factors also has the is for to and S phase of the cell cycle L. L. F. S. G. PubMed Scopus Google Scholar). E2F1 can cell cycle and apoptosis Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar), and deregulated E2F1 can cooperate with p53 to apoptosis X. Levine A.J. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar, Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar, J. G. A. L. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar). E2F1 can of p53 cofactors including damage of and are to as M. Oren M. Cell 2005; PubMed Scopus Google Scholar). promotes apoptosis by p53 at S. M. Mol. 8: PubMed Scopus Google Scholar), of p53 to the of proapoptotic genes G. S. L. Lu X. Mol. 8: PubMed Scopus Google Scholar). the the activation of p53 first G1 phase arrest by E2F1 via G. R. J. R. J. 2005; PubMed Scopus Google Scholar). E2F1 with p53 for cell cycle with p53 in apoptosis E2F1 levels can a by growth factors G. S. L. Nat. Cell Biol. 2008; PubMed Scopus (291) Google Scholar). the of p53 and E2F1 switching to the decision between cell and death after DNA damage. It is also to the of p53 cofactors on was in the for p53 by the we model to cell cycle and cell fate decision are by p53 and E2F1 in the DNA damage response. model is of a DNA a p53 and a cell fate decision model can the process the of DNA damage to the of cell We found that the cell fate is determined by the number of p53 on the extent of DNA damage for of growth E2F1 apoptosis in two it p53 cofactors to p53 and it the levels of to make cells sensitive to death We that activation of E2F1 or p53 in and G1 arrest, whereas activation of p53 and E2F1 response to DNA damage can be as a and the signaling pathways involved are rather It is to to in the process of DNA damage response. Here, we on the for cell fate experimental our model was on and We also to cross-talk between the p53 and E2F1 pathways R. R. N. M. G. N. G. R. J. R. 2008; 9: PubMed Scopus Google Scholar). of the model are as for Cell in to DNA model for the p53 of DNA damage is in cells to DNA the and of DNA damage, is Upon is activated by as a of DNA damage (6Ma L. Wagner J. Rice J.J. Hu W. Levine A.J. Stolovitzky G.A. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 14266-14271Crossref PubMed Scopus (291) Google Scholar, M.B. PubMed Scopus Google Scholar). p53 is activated by J. 2004; PubMed Scopus Google Scholar), and and negative feedback loops p53 and p53 pulses J.J. Cell 2007; PubMed Scopus Google Scholar). p53 is between p53 and p53 to cell cycle arrest and J.J. Cell 2007; PubMed Scopus Google Scholar, F. W. Proc. Natl. Acad. Sci. U.S.A. 2009; PubMed Scopus Google Scholar). activated by growth factors, E2F1 can the the G1 to S phase and cooperate with p53 to apoptosis. to E. A. G. Mol. 2008; PubMed Scopus Google Scholar), a negative feedback the to the In the we the of is the of DNA damage induced by PubMed Scopus Google Scholar). to experimental of may cell G. A. F. M. M. L. D.P. 2005; PubMed Scopus Google Scholar). in a in the and of is of (6Ma L. Wagner J. Rice J.J. Hu W. Levine A.J. Stolovitzky G.A. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 14266-14271Crossref PubMed Scopus (291) Google that in to the is the for repair, in the G1 phase S. DNA PubMed Scopus Google Scholar). We the process a process that is by of to a and by irreversible process the to we the model PubMed Scopus Google and the proposed by (6Ma L. Wagner J. Rice J.J. Hu W. Levine A.J. Stolovitzky G.A. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 14266-14271Crossref PubMed Scopus (291) Google to the process and we a population of cells that are to the is to the of Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar, N. M. J. Biol. PubMed Scopus Google Scholar), the of are to the with a of are than in (6Ma L. Wagner J. Rice J.J. Hu W. Levine A.J. Stolovitzky G.A. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 14266-14271Crossref PubMed Scopus (291) Google Scholar), it is that are in p53 a role in DNA repair, role in is and S. Nat. Rev. Mol. Cell Biol. 2005; PubMed Scopus Google Scholar). revealed that p53 can the of DNA with N. S. N. S. PubMed Scopus Google Scholar, W. Google Scholar), whereas of p53 on were also reported N. S. A. U. K.H. L. Mol. Biol. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). For we the of p53 on DNA role of as a of DNA damage has been M.B. PubMed Scopus Google Scholar, 2005; PubMed Scopus Google Scholar). In as a and is Upon can be by and leads to of 2005; PubMed Scopus Google Scholar). a feedback in promotes the of M.B. PubMed Scopus Google Scholar). Thus, the activation of is by a 2009; PubMed Scopus Google Scholar, A. A. J. 2007; Scopus Google Scholar). 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Sigal A. Dekel E. Yarnitzky G. Alon U. Mol. Biol. PubMed Scopus Google fate can be governed by signaling pathways p53 and Both p53 and E2F1 function as transcription It has been that and cofactors the of p53 (2Murray-Zmijewski F. Slee E.A. Lu X. Nat. Rev. Mol. Cell Biol. 2008; 9: 702-712Crossref PubMed Scopus (331) Google Scholar). E2F1 can the levels of p53 cofactors and proapoptotic M. Oren M. Cell 2005; PubMed Scopus Google Scholar, J. M. Nat. Cell Biol. PubMed Scopus Google Scholar). of are in and are as fate decision p53 is p53 and p53 p53 is a primarily of p53 on and whereas p53 is a of p53 on p53 cell cycle arrest in the G1 phase by E2F1 whereas p53 expression of proapoptotic between p53 and p53 is by and E2F1 can be activated by growth p53 and E2F1 cooperate to the of p53 expression of and in E2F1 promotes apoptosis by up-regulating proapoptotic factors including and and the of p53 expression of genes Nat. Rev. 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Nat. Rev. Cancer. PubMed Scopus Google Scholar), it is that and can cooperate to the is with to the that as a for activation Cell 2007; PubMed Scopus Google Scholar). is activated by and of the and of such as and also a role in their are for Proc. Natl. Acad. Sci. U.S.A. 2008; PubMed Scopus Google Scholar, S. Cell PubMed Scopus Google of are by in are on the model by G. S. L. Nat. Cell Biol. 2008; PubMed Scopus (291) Google Scholar). We that is induced by p53 the p53 with the between p53 and p53 is by and are factors in process the of is by is by and M. Oren M. Cell 2005; PubMed Scopus Google Scholar, S. M. Mol. 8: PubMed Scopus Google Scholar). We that is with a of p53 with a of and p53 and with a of J.J. Cell 2007; PubMed Scopus Google Scholar). This that level pulses of p53 and after p53 is of and is to be by p53 and G. S. L. Lu X. Mol. 8: PubMed Scopus Google Scholar, 2000; 102: PubMed Scopus Google Scholar), is governed by E2F1 M. Oren M. 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We found that or of the by can the of cell cycle arrest and apoptosis by In our that the of and and is crucial for activation of the cross-talk between the p53 and E2F1 pathways the between cell cycle and cell fate is of for tumor proposed that cell fate is determined by the number of p53 pulses F. W. Proc. Natl. Acad. Sci. U.S.A. 2009; PubMed Scopus Google Scholar), we the cross-talk between p53 and transcription It is to of cell cycle in cell fate For Cell 2008; PubMed Scopus Google the decision between arrest, G1 arrest, and apoptosis in a model of the G1 the between the and pathways in cell cycle and the between p53 and E2F1 in the in cell cycle and cell fate decision are by the p53 and E2F1 is that E2F1 is a of L. L. F. S. G. PubMed Scopus Google and can cooperate with p53 to apoptosis X. Levine A.J. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar). In work we on the role of E2F1 in the p53-mediated response to DNA damage in serum medium. that can also and p53 by oncogene activation S. F. G. K.H. PubMed Scopus Google Scholar). Upon DNA damage, p53 is activated by Thus, we the activation of p53 by our cross-talk between the p53 and E2F1 pathways is in two the E2F1 the between the two of i.e. p53 and p53 p53 cell cycle arrest, whereas growth can cells to overcome cell cycle arrest and E2F1 expression of promotes the of p53 the the of and by E2F1 is crucial for apoptosis. our that E2F1 can p53-mediated apoptosis by p53 apoptosis and the of apoptosis. are in with experimental observations M. Oren M. Cell 2005; PubMed Scopus Google Scholar, J. M. Nat. Cell Biol. PubMed Scopus Google that the phase of the cell cycle is with cell are by p53 and We showed that transient G1 arrest by E2F1 time for DNA and cell Thus, G1 arrest a mechanism for cells with damage. This is different the that the role of is with to apoptosis by or F. PubMed Scopus Google Scholar, Mol. Google Scholar). In the we that it is for to cell by the of It was that cell cycle arrest by pulses can make cells to death the our that may be for apoptosis in response to DNA damage. S phase to or oncogene activation cells sensitive to DNA damage. it has been reported that oncogene activation is to as as deregulated E2F1 X. Levine A.J. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar, Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar, J. G. A. L. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar). In apoptosis is also with M. DNA PubMed Scopus Google Scholar). the mechanism for the of with apoptosis still to be explored work may provide clues to the and of It is that E2F1 is deregulated in cancer cells to Nat. Rev. Cancer. PubMed Scopus Google Scholar). the p53 is by in than of (3Vousden K.H. Lane D.P. Nat. Rev. Mol. Cell Biol. 2007; 8: 275-283Crossref PubMed Scopus (1707) Google Scholar). Thus, cancer cells with deregulated E2F1 and p53 may be by p53 J. Mol. PubMed Scopus Google Scholar). It is that of p53 transient growth arrest in cells or apoptosis in cancer Thus, the tumor cells also the in our that oncogene such as may be to E2F1 as to the tumor cells with in with p53. it is still a to that of cross-talk between the p53 and E2F1 the work we reported the of cell cycle and cell fate decision by p53 and E2F1 in response to DNA damage. In E2F1 is activated to cell is activated to p53 In is by p53. p53 pulses cell cycle arrest E2F1 whereas cell cycle arrest by growth factors leads to the activation of with p53 to initiate apoptosis. work the between cell cycle and cell fate decision and may provide clues to cancer IntroductionThe tumor suppressor p53 has a crucial role in preventing tumorigenesis (1Meek D.W. Nat. Rev. Cancer. 2009; 9: 714-723Crossref PubMed Scopus (487) Google Scholar). Upon various stresses, p53 is stabilized and activated to function primarily as a transcription factor, regulating the expression of a large number of genes involved in cell cycle arrest, DNA repair, or apoptosis (2Murray-Zmijewski F. Slee E.A. Lu X. Nat. Rev. Mol. Cell Biol. 2008; 9: 702-712Crossref PubMed Scopus (331) Google Scholar). Thus, p53 is at the hub of numerous signaling pathways triggered by various stresses. Previously, it was proposed that cell fate after DNA damage is governed by p53 levels, i.e. a low level of p53 leads to transient growth arrest and cell survival, whereas a high level promotes irreversible apoptosis (3Vousden K.H. Lane D.P. Nat. Rev. Mol. Cell Biol. 2007; 8: 275-283Crossref PubMed Scopus (1707) Google Scholar). Recently, it has been reported that p53 levels can exhibit oscillations in response to DNA damage induced by ionizing radiation (IR) (4Lev Bar-Or R. Maya R. Segel L.A. Alon U. Levine A.J. Oren M. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 11250-11255Crossref PubMed Scopus (479) Google Scholar, 5Lahav G. Rosenfeld N. Sigal A. Geva-Zatorsky N. Levine A.J. Elowitz M.B. Alon U. Nat. Genet. 2004; 36: 147-150Crossref PubMed Scopus (804) Google Scholar). Whereas damped oscillations of p53 levels were observed at the population level (4Lev Bar-Or R. Maya R. Segel L.A. Alon U. Levine A.J. Oren M. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 11250-11255Crossref PubMed Scopus (479) Google Scholar), a series of undamped pulses was observed at the single-cell level (5Lahav G. Rosenfeld N. Sigal A. Geva-Zatorsky N. Levine A.J. Elowitz M.B. Alon U. Nat. Genet. 2004; 36: 147-150Crossref PubMed Scopus (804) Google Scholar). In such a digital mode, it is the number of p53 pulses rather than their amplitudes and duration that is related to the extent of DNA damage and determines cell fate (5Lahav G. Rosenfeld N. Sigal A. Geva-Zatorsky N. Levine A.J. Elowitz M.B. Alon U. Nat. Genet. 2004; 36: 147-150Crossref PubMed Scopus (804) Google Scholar). p53 pulses can be generated by negative feedback loops with time delay (6Ma L. Wagner J. Rice J.J. Hu W. Levine A.J. Stolovitzky G.A. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 14266-14271Crossref PubMed Scopus (291) Google Scholar, 7Geva-Zatorsky N. Rosenfeld N. Itzkovitz S. Milo R. Sigal A. Dekel E. Yarnitzky G. Alon U. Mol. Biol. PubMed Scopus Google Scholar, E. A. G. Mol. 2008; PubMed Scopus Google or and negative feedback loops A. J.J. Cell 2005; PubMed Scopus Google Scholar, J.J. Cell 2007; PubMed Scopus Google cells p53 pulses to various different is explored the of p53 pulses in response to DNA damage. and J.J. Cell 2007; PubMed Scopus Google p53 to and showed that p53 pulses the decision between cell cycle and apoptosis. We model of the p53 signaling to the process the of DNA damage to the of cell that two of p53 in cell fate decision F. W. Proc. Natl. Acad. Sci. U.S.A. 2009; PubMed Scopus Google Scholar). E. A. G. Nat. Rev. Cancer. 2009; 9: PubMed Scopus Google proposed that p53 pulses can for a of expression of that the pulsatile response of p53 may a and mechanism by can be the different by p53 are with p53 is to cell fate cross-talk between p53 and transcription factors also has the is for to and S phase of the cell cycle L. L. F. S. G. PubMed Scopus Google Scholar). E2F1 can cell cycle and apoptosis Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar), and deregulated E2F1 can cooperate with p53 to apoptosis X. Levine A.J. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar, Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar, J. G. A. L. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar). E2F1 can of p53 cofactors including damage of and are to as M. Oren M. Cell 2005; PubMed Scopus Google Scholar). promotes apoptosis by p53 at S. M. Mol. 8: PubMed Scopus Google Scholar), of p53 to the of proapoptotic genes G. S. L. Lu X. Mol. 8: PubMed Scopus Google Scholar). the the activation of p53 first G1 phase arrest by E2F1 via G. R. J. R. J. 2005; PubMed Scopus Google Scholar). E2F1 with p53 for cell cycle with p53 in apoptosis E2F1 levels can a by growth factors G. S. L. Nat. Cell Biol. 2008; PubMed Scopus (291) Google Scholar). the of p53 and E2F1 switching to the decision between cell and death after DNA damage. It is also to the of p53 cofactors on was in the for p53 by the we model to cell cycle and cell fate decision are by p53 and E2F1 in the DNA damage response. model is of a DNA a p53 and a cell fate decision model can the process the of DNA damage to the of cell We found that the cell fate is determined by the number of p53 on the extent of DNA damage for of growth E2F1 apoptosis in two it p53 cofactors to p53 and it the levels of to make cells sensitive to death We that activation of E2F1 or p53 in and G1 arrest, whereas activation of p53 and E2F1 apoptosis.