ERK Activation Mediates Cell Cycle Arrest and Apoptosis after DNA Damage Independently of p53

In response to DNA damage, ataxia-telangiectasia mutant and ataxia-telangiectasia and Rad-3 activate p53, resulting in either cell cycle arrest or apoptosis. We report here that DNA damage stimuli, including etoposide (ETOP), adriamycin (ADR), ionizing irradiation (IR), and ultraviolet irradiation (UV) activate ERK1/2 (ERK) mitogen-activated protein kinase in primary (MEF and IMR90), immortalized (NIH3T3) and transformed (MCF-7) cells. ERK activation in response to ETOP was abolished in ATM−/− fibroblasts (GM05823) and was independent of p53. The MEK1 inhibitor PD98059 prevented ERK activation but not p53 stabilization. Maximal ERK activation in response to DNA damage was not attenuated in MEFp53−/−. However, ERK activation contributes to either cell cycle arrest or apoptosis in response to low or high intensity DNA insults, respectively. Inhibition of ERK activation by PD98059 or U0126 attenuated p21CIP1 induction, resulting in partial release of the G2/M cell cycle arrest induced by ETOP. Furthermore, PD98059 or U0126 also strongly attenuated apoptosis induced by high dose ETOP, ADR, or UV. Conversely, enforced activation of ERK by overexpression of MEK-1/Q56P sensitized cells to DNA damage-induced apoptosis. Taken together, these results indicate that DNA damage activates parallel ERK and p53 pathways in an ATM-dependent manner. These pathways might function cooperatively in cell cycle arrest and apoptosis. In response to DNA damage, ataxia-telangiectasia mutant and ataxia-telangiectasia and Rad-3 activate p53, resulting in either cell cycle arrest or apoptosis. We report here that DNA damage stimuli, including etoposide (ETOP), adriamycin (ADR), ionizing irradiation (IR), and ultraviolet irradiation (UV) activate ERK1/2 (ERK) mitogen-activated protein kinase in primary (MEF and IMR90), immortalized (NIH3T3) and transformed (MCF-7) cells. ERK activation in response to ETOP was abolished in ATM−/− fibroblasts (GM05823) and was independent of p53. The MEK1 inhibitor PD98059 prevented ERK activation but not p53 stabilization. Maximal ERK activation in response to DNA damage was not attenuated in MEFp53−/−. However, ERK activation contributes to either cell cycle arrest or apoptosis in response to low or high intensity DNA insults, respectively. Inhibition of ERK activation by PD98059 or U0126 attenuated p21CIP1 induction, resulting in partial release of the G2/M cell cycle arrest induced by ETOP. Furthermore, PD98059 or U0126 also strongly attenuated apoptosis induced by high dose ETOP, ADR, or UV. Conversely, enforced activation of ERK by overexpression of MEK-1/Q56P sensitized cells to DNA damage-induced apoptosis. Taken together, these results indicate that DNA damage activates parallel ERK and p53 pathways in an ATM-dependent manner. These pathways might function cooperatively in cell cycle arrest and apoptosis. phosphatidylinositol 3-kinase mitogen-activated protein kinase extracellular signal-regulated kinase MAPK/ERK kinase c-Jun NH2-terminal kinase etoposide adriamycin ionizing irradiation ultraviolet irradiation fetal calf serum terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling fluorescence-activate cell sorting ataxia-telangiectasia mutant ataxia-telangiectasia and Rad-3 mouse embryonic fibroblasts Eukaryotic cells employ multiple mechanisms to ensure accurate transmission of genetic information between generations. Critical surveillance of this transmission is provided by the DNA damage response, which may arrest the cell cycle to allow damage repair or direct cells to apoptosis in situations of severe damage (1.Lowe S.W. Schmitt E.M. Smith S.W. Osborne B.A. Jacks T. Nature. 1993; 362: 847-849Crossref PubMed Scopus (2753) Google Scholar, 2.Lozano G. Elledge S.J. Nature. 2000; 404: 24-25Crossref PubMed Scopus (110) Google Scholar, 3.Tanaka H. Arakawa H. Yamaguchi T. Shiraishi K. Fukuda S. Matsui K. Takei Y. Nakamura Y. Nature. 2000; 404: 42-49Crossref PubMed Scopus (735) Google Scholar, 4.Zhou B.B. Elledge S.J. Nature. 2000; 408: 433-439Crossref PubMed Scopus (2596) Google Scholar). Our understanding of how cells sense DNA damage remains incomplete, but it is clear that two members of the phosphatidylinositol 3-kinase (PI3K)1 family, ATM and ATR, are major DNA damage signal transducers (4.Zhou B.B. Elledge S.J. Nature. 2000; 408: 433-439Crossref PubMed Scopus (2596) Google Scholar). Downstream of ATM/ATR lies p53, a central mediator of the response, which in turn induces cell cycle arrest by up-regulation of p21CIP1 and 14-3-3ς, activates DNA damage repair pathways, and induces apoptosis (5.Caspari T. Curr. Biol. 2000; 10: R315-R317Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 6.Colman M.S. Afshari C.A. Barrett J.C. Mutat. Res. 2000; 462: 179-188Crossref PubMed Scopus (149) Google Scholar). p53 is normally rapidly degraded by Mdm2-mediated ubiquitin-dependent proteolysis (7.Haupt Y. Maya R. Kazaz A. Oren M. Nature. 1997; 387: 296-299Crossref PubMed Scopus (3629) Google Scholar, 8.Kubbutat M.H. Jones S.N. Vousden K.H. Nature. 1997; 387: 299-303Crossref PubMed Scopus (2798) Google Scholar). In response to DNA damage, p53 is stabilized by inhibition of this proteolytic process, partly through post-translational phosphorylation. Stabilization of p53 by phosphorylation on residues Ser-15 and Ser-21 by ATM and Chk2 kinase in response to DNA damage is well described (9.Banin S. Moyal L. Shieh S. Taya Y. Anderson C.W. Chessa L. Smorodinsky N.I. Prives C. Reiss Y. Shiloh Y. Ziv Y. Science. 1998; 281: 1674-1677Crossref PubMed Scopus (1688) Google Scholar, 10.Canman C.E. Lim D.S. Cimprich K.A. Taya Y. Tamai K. Sakaguchi K. Appella E. Kastan M.B. Siliciano J.D. Science. 1998; 281: 1677-1679Crossref PubMed Scopus (1684) Google Scholar, 11.Hirao A. Kong Y.Y. Matsuoka S. Wakeham A. Ruland J. Yoshida H. Liu D. Elledge S.J. Mak T.W. Science. 2000; 287: 1824-1827Crossref PubMed Scopus (1032) Google Scholar). Members of the mitogen-activated protein kinase (MAPK) family have also been demonstrated to phosphorylate and stabilize p53 (12.Fuchs S.Y. Adler V. Buschmann T. Yin Z. Wu X. Jones S.N. Ronai Z. Genes Dev. 1998; 12: 2658-2663Crossref PubMed Scopus (278) Google Scholar, 13.Huang C. Ma W.Y. Maxiner A. Sun Y. Dong Z. J. 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J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). The of DNA damage-induced ERK activation in apoptosis also not been J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, X. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). In this with ERK activation apoptosis ERK is R. S. K. T. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to ERK activation in response to DNA damage, and to the mechanisms and of We report here that multiple DNA damage stimuli, including etoposide (ETOP), adriamycin (ADR), ultraviolet irradiation and ionizing activate ERK in cell We that this on ATM and is independent of p53. that ERK activation with p53 to to apoptosis or cell cycle the report to an ERK-mediated DNA damage and ETOP, ADR, and The MEK1 PD98059 and and respectively. of ETOP, ADR, and U0126 in and the was NIH3T3 and cells in with fetal calf serum in a MEF and in and was and in and The was the and in with and and The in the was provided by Lowe of A.W. Barradas M. Stone J.C. van Aelst L. Serrano M. Lowe S.W. Genes Dev. 1998; 12: 3008-3019Crossref PubMed Scopus (751) Google Scholar). and by of and have D. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). was have shown D. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, D. H. Ruland J. Liu L. V. Mak T.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a DNA was and to cells. cells in a with of The was and through a of the was to NIH3T3 cells to was with to DNA damage cells in a and of cell was on and with and with the an and and DNA and have D. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, D. H. Ruland J. Liu L. V. Mak T.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). the cell cells in and with DNA damage with or PD98059 or U0126 or the cell proliferation was and cells cell with a cycle was by NIH3T3 cells with in the of by of signals cell sorting have A. Kong Y.Y. Matsuoka S. Wakeham A. Ruland J. Yoshida H. Liu D. Elledge S.J. Mak T.W. Science. 2000; 287: 1824-1827Crossref PubMed Scopus (1032) Google Scholar). to on a with ETOP the was and cells in and in a and with DNA The was a To ERK is by DNA damage MEF cells with ETOP, which induces DNA by interfering with the function of DNA B. S. J. PubMed Scopus Google Scholar). ETOP induced of p53 and up-regulation of p21CIP1 not ETOP induced ERK activation by with two The of ERK activation and of ETOP the in response to ETOP ETOP in of ERK activation with ERK activation observed or not a between intensity of DNA damage and of ERK To ERK activation is a of ETOP or MEF multiple DNA damage to ERK ETOP, ADR, and UV to ERK activation in primary immortalized and transformed cells and also ERK in MEF and not that DNA damage leads to ERK ERK activation is to phosphorylation on and by P. J. T.W. J. 10: PubMed Scopus Google Scholar, E. H. C.A. D. M.H. J. Biol. Chem. 1993; Full Text PDF PubMed Google to DNA damage-induced ERK activation also of the MEK1 PD98059 and U0126 not prevented ERK of ERK activation was also observed cells with PD98059 or U0126 to ADR, or not the of MEK1 in DNA damage-induced ERK Taken together, these results that ERK activation is a of cellular DNA damage by ATM a central in the of DNA damage signals (4.Zhou B.B. Elledge S.J. Nature. 2000; 408: 433-439Crossref PubMed Scopus (2596) Google and ATM been shown to a in the DNA damage-induced activation of JNK and p38 A. J. R. S. Res. 1995; Google Scholar, X. M. L. C. Y. S. J. Cell. Biol. 2000; PubMed Scopus Google to ATM a in DNA damage-induced ERK a member of the family, the kinase of ATM is by the W. R. M.S. P. J. Taya Y. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, Res. 1998; Google Scholar). of ETOP but not ERK activation not with the that the kinase of ATM but not Res. 1998; Google and that DNA damage are To ATM of ERK ATM−/− (GM05823) and fibroblasts of ATM in but not in was by an not of or ETOP to cells to p53 with phosphorylation on Ser-15 and up-regulation of p21CIP1 Ser-15 p53 was and was abolished in cells in response to or ETOP the of ATM function in the ATM−/− ERK activation was in but in a of ATM in ERK However, ERK activation was not attenuated in the ATM−/− that might also an in this which ATM and P. Taya Y. Res. 1999; Google ERK activation in this the that a in the transmission of DNA damage to ERK not p53 is the major protein of ATM the DNA damage response, to ERK activation a in the p53 been by (25.Persons D.L. Yazlovitskaya E.M. Pelling J.C. J. Biol. Chem. 2000; 275: 35778-35785Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar, S.W. L. M. T. Lu S.A. S. A. 2000; PubMed Scopus Google Scholar, Dong Z. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). p53 by ETOP and and not ERK activation in cell cells. MEK1 inhibition with PD98059 ERK activation but was on p53 in response to DNA damage in and cells that ERK activation was not of p53. Conversely, of cells with to p53 prevented ETOP not and p53 but not ERK that ERK activation is not of p53. However, that ERK activation may either Dong Z. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google or S.W. L. M. T. Lu S.A. S. A. 2000; PubMed Scopus Google of p53 DNA damage, to In of a of ERK activation was not attenuated in with MEF the of ERK activation is in to of ERK in these cells and UV also induced ERK activation in not Taken together, these indicate that DNA damage-induced ERK activation is independent of p53. The two cellular to DNA damage are cell cycle arrest the damage to or apoptosis in response to low or high of DNA damage, respectively. The is in this and a major in cells in either or G2/M in response to DNA damage F. A. C. T. S. B. Science. 1998; PubMed Scopus Google Scholar, C. P. Elledge S.J. P. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar). We have observed that ERK activation and p21CIP1 in a p53 DNA damage not that ERK activation might is with the that enforced ERK activation by overexpression of a to p21CIP1 D. D. H. E. E. M. Cell. Biol. 1997; PubMed Scopus Google A. B. H. Cell. Biol. 1997; PubMed Scopus Google Scholar). the of inhibition of ERK activation on p21CIP1 DNA damage. Inhibition of ERK activation by PD98059 p21CIP1 by and but on p53 by ETOP PD98059 also attenuated p21CIP1 overexpression of a A.W. Barradas M. Stone J.C. van Aelst L. Serrano M. Lowe S.W. Genes Dev. 1998; 12: 3008-3019Crossref PubMed Scopus (751) Google strongly ERK in NIH3T3 and MEF cells not and to p21CIP1 that was also by PD98059 Furthermore, of in cells also in not that ERK activation is of p21CIP1 with with D. D. H. E. E. M. Cell. Biol. 1997; PubMed Scopus Google Scholar, A. B. H. Cell. Biol. 1997; PubMed Scopus Google Scholar). Our is the to p21CIP1 by ERK ERK activation contributes to p21CIP1 and and p21CIP1 an in of arrest C. P. Elledge S.J. P. Cell. 1995; Full Text PDF PubMed Scopus Google and of arrest the G2/M F. A. C. T. S. B. Science. 1998; PubMed Scopus Google to the of p21CIP1 induced by ERK activation a in cell cycle arrest in response to DNA damage. PD98059 results a of arrest with the that ERK M. V. C.J. S. A. 1998; 95: PubMed Scopus Google of PD98059 to ETOP to a release the G2/M arrest with etoposide We that G2/M release was by labeling with and an of cells to PD98059 is to ETOP not To a of ERK in G2/M arrest in response to ETOP, a MEK1 was also U0126 a on and U0126 ETOP G2/M arrest results observed with not the of PD98059 on cell cycle arrest induced by is that induced by ETOP, with the that inhibition of ERK activation was in p21CIP1 a cycle arrest function of ERK in response to DNA damage, to DNA damage-induced ERK activation also mediated of ETOP to DNA in NIH3T3 which was prevented by ERK inhibition of the or also prevented apoptosis in response to ETOP, that the cellular a in DNA damage-induced apoptosis of apoptosis terminal labeling that of cells to ETOP and that ERK inhibition with this to a major ERK in DNA damage-induced apoptosis in response to ETOP or overexpression also apoptosis to the importance of the results also U0126 was U0126 induced of and strongly apoptosis was to cells in ETOP in apoptosis and U0126 or this to and not the importance of ERK in activation DNA damage-induced apoptosis. NIH3T3 cells with U0126 ETOP U0126 ETOP or U0126 ETOP with by of cells with DNA are and the of cells in this is shown are of We that ERK is central in of apoptosis in response to DNA damage, overexpression of ERK cells to to ETOP. Indeed, apoptosis in NIH3T3 cells with a A.W. Barradas M. Stone J.C. van Aelst L. Serrano M. Lowe S.W. Genes Dev. 1998; 12: 3008-3019Crossref PubMed Scopus (751) Google in response to ETOP a with apoptosis in NIH3T3 cells with Inhibition of with PD98059 prevented this that ERK was by a of DNA damage to ensure that through ERK was a response to DNA damage. the of PD98059 on and cell also Inhibition of ERK activation by PD98059 cell in response to UV and and Taken together, these results that ERK activation DNA damage-induced apoptosis. DNA damage surveillance an in in or of of these pathways results in genetic and may to the of multiple genetic and of C. B. Nature. 1998; PubMed Scopus Google Scholar, B. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, J. S. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). genetic C. B. Nature. 1998; PubMed Scopus Google and of p53, a major in DNA damage pathways, in of Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). of a ATM the of DNA damage, is also by in response to DNA damage and the of cancer Y. T. M.S. D. Genes Dev. 10: PubMed Scopus Google Scholar, B.A. Res. Google Scholar). In this information to an DNA damage We observed that DNA damage to ERK activation by ERK phosphorylation in cell and the of ERK activation with the intensity of DNA damage. is with that of cells with and cisplatin to ERK activation (25.Persons D.L. Yazlovitskaya E.M. Pelling J.C. J. Biol. Chem. 2000; 275: 35778-35785Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar, S.W. L. M. T. Lu S.A. S. A. 2000; PubMed Scopus Google Scholar, X. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). Our result of the mechanisms and of ERK activation DNA damage. We have ERK activation to of ATM in response to ETOP, independent of p53 and with p53, ERK activation to DNA damage-induced cell cycle arrest and apoptosis. DNA damage activates the kinase of which a of (4.Zhou B.B. Elledge S.J. Nature. 2000; 408: 433-439Crossref PubMed Scopus (2596) Google including the phosphorylation of Ser-15 the of p53 (9.Banin S. Moyal L. Shieh S. Taya Y. Anderson C.W. Chessa L. Smorodinsky N.I. Prives C. Reiss Y. Shiloh Y. Ziv Y. Science. 1998; 281: 1674-1677Crossref PubMed Scopus (1688) Google Scholar, 10.Canman C.E. Lim D.S. Cimprich K.A. Taya Y. Tamai K. Sakaguchi K. Appella E. Kastan M.B. Siliciano J.D. Science. 1998; 281: 1677-1679Crossref PubMed Scopus (1684) Google Scholar). ubiquitin-dependent p53 by interfering with the between p53 and Mdm2 C. Cell. 1998; 95: Full Text Full Text PDF PubMed Scopus Google Scholar, S.Y. M. Taya Y. Prives C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). We report here that ETOP is to activate ERK in ATM−/− fibroblasts but in that ERK is a of ATM in response to DNA damage. this is that a also ERK it been that ATM kinase in the to protein by Kastan M.B. Biol. 2000; PubMed Scopus Google the that the of ATM in cell may not to the of the that ERK might also a of ATM and the of a ATM kinase might with ERK activation and cell with the that ATM−/− cells and high of growth Biol. 2000; PubMed Scopus Google Scholar). To this have observed that of or also the of ERK D. A. J. M. L. B. V. J. T. W. and A. J. the of and ATM kinase are and W. R. M.S. P. J. Taya Y. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, Res. 1998; Google Scholar, A. Biochem. J. 1993; PubMed Scopus Google these indicate a ATM in cell by ERK p53 protein is a major in the DNA damage response, it is to between p53 and ERK activation DNA damage. ERK activation leads to p53 activation in primary but not immortalized MEF A.W. Barradas M. Stone J.C. van Aelst L. Serrano M. Lowe S.W. Genes Dev. 1998; 12: 3008-3019Crossref PubMed Scopus (751) Google Scholar, E. F. Shieh S.Y. G. Prives C. C.J. Lowe S.W. Genes Dev. 1998; 12: PubMed Scopus Google Scholar, T. F. G. C.J. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, M. A.W. D. Lowe S.W. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, F. T. C.J. Genes Dev. 1998; 12: PubMed Scopus Google Scholar). In the of DNA damage response, have that ERK activation of p53. is on the MEK1 prevented ERK activation but not p53 in response to DNA damage with to p53 DNA damage-induced p53 but not ERK activation and the of ERK activation by ETOP, and was not attenuated in is with the that enforced activation of ERK leads to cell cycle arrest in a D. D. H. E. E. M. Cell. Biol. 1997; PubMed Scopus Google Scholar, A. B. H. Cell. Biol. 1997; PubMed Scopus Google Our results are different that ERK activation lies either or of p53 in response to DNA damage Inhibition of ERK activation by PD98059 was to p53 by phosphorylation of Ser-15 in the of p53 (25.Persons D.L. Yazlovitskaya E.M. Pelling J.C. J. Biol. Chem. 2000; 275: 35778-35785Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar). it was not the by with p53, ERK p53 on is how a phosphorylate Ser-15 of p53, this is not by a but a Furthermore, ERK activation by a growth factor that ERK activation might not to DNA damage X. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). However, the remains that these may to the different DNA damage is by that and ERK activation was abolished in a cell S.W. L. M. T. Lu S.A. S. A. 2000; PubMed Scopus Google in this p53 of ERK In of the that p53 is some of DNA damage-induced ERK S.W. L. M. T. Lu S.A. S. A. 2000; PubMed Scopus Google that overexpression of p53 to ERK this is that overexpression of p53 leads to activation of a DNA damage response resulting in ATM kinase ATM kinase in turn leads to ERK with that ERK activation on ATM DNA damage. this was the that overexpression of p53 to activation of p53 S.W. L. M. T. Lu S.A. S. A. 2000; PubMed Scopus Google Scholar). However, it is that the of p53 is to activate p53 T. J.D. G. F. C.J. S. A. 1998; 95: PubMed Scopus Google Scholar). independent of p53, that ERK activation to cell cycle arrest and DNA damage. Inhibition of ERK activation by PD98059 or U0126 not p21CIP1 induction, the partial release by these cell cycle arrest in response to low of either ETOP or not p21CIP1 is to G2/M arrest F. A. C. T. S. B. Science. 1998; PubMed Scopus Google Scholar). enforced activation of ERK is to to p21CIP1 in a D. D. H. E. E. M. Cell. Biol. 1997; PubMed Scopus Google Scholar, A. B. H. Cell. Biol. 1997; PubMed Scopus Google demonstration here is the that ERK activation contributes to the of p21CIP1 In response to of ETOP, ADR, and inhibition of ERK activation by PD98059 and U0126 attenuated apoptosis and DNA damage-induced cell cycle arrest and apoptosis p53, results indicate the of a parallel also in DNA damage-induced cell cycle arrest and apoptosis. The here that ERK activation DNA damage a in surveillance and response to DNA damage, of p53. cells high of ERK these may the of some transformed cells to with primary cells. to of of the ERK We the of by ERK activation cell cycle arrest and apoptosis DNA damage of of was by a the and by of V. J. PDF

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