Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation.

Previous work has established a role for p53 in triggering apoptosis in response to DNA damage; p53 also induces apoptosis in response to deregulation of the Rb cell cycle pathway. The latter event is consistent with a role for the Rb-regulated E2F1 protein as a specific inducer of apoptosis and p53 accumulation. We now show that DNA damage leads to a specific induction of E2F1 accumulation, dependent on ATM kinase activity and that the specificity of E2F1 induction reflects a specificity in the phosphorylation of E2F1 by ATM as well as the related kinase ATR. We identify a site for ATM/ATR phosphorylation in the amino terminus of E2F1 and we show that this site is required for ATM-mediated stabilization of E2F1. Finally, we also show that E2F1 is required for DNA damaged induced apoptosis in mouse thymocytes. We conclude that the cellular response to DNA damage makes use of signals from the Rb/E2F cell cycle pathway.

[1]  M E Greenberg,et al.  Myc requires distinct E2F activities to induce S phase and apoptosis. , 2001, Molecular cell.

[2]  A. Caron,et al.  E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. , 2001, Genes & development.

[3]  B. Pützer,et al.  Role of the p53-homologue p73 in E2F1-induced apoptosis , 2000, Nature Genetics.

[4]  W. Kaelin,et al.  A common E2F-1 and p73 pathway mediates cell death induced by TCR activation , 2000, Nature.

[5]  David I. Smith,et al.  Role for the p53 homologue p73 in E2F-1-induced apoptosis , 2000, Nature.

[6]  D. Chan,et al.  Utilization of Oriented Peptide Libraries to Identify Substrate Motifs Selected by ATM* , 2000, The Journal of Biological Chemistry.

[7]  J. Nevins,et al.  Identification of a Novel E2F3 Product Suggests a Mechanism for Determining Specificity of Repression by Rb Proteins , 2000, Molecular and Cellular Biology.

[8]  Bo Xu,et al.  ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway , 2000, Nature.

[9]  S. Elledge,et al.  DNA damage-induced activation of p53 by the checkpoint kinase Chk2. , 2000, Science.

[10]  T. Halazonetis,et al.  Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. , 2000, Genes & development.

[11]  Y Taya,et al.  The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. , 2000, Genes & development.

[12]  S. T. Kim,et al.  Substrate Specificities and Identification of Putative Substrates of ATM Kinase Family Members* , 1999, The Journal of Biological Chemistry.

[13]  S. Elledge,et al.  A family of mammalian F-box proteins , 1999, Current Biology.

[14]  K. Helin,et al.  CDC25A Phosphatase Is a Target of E2F and Is Required for Efficient E2F-Induced S Phase , 1999, Molecular and Cellular Biology.

[15]  C. Blattner,et al.  Transcription Factor E2F-1 Is Upregulated in Response to DNA Damage in a Manner Analogous to That of p53 , 1999, Molecular and Cellular Biology.

[16]  M. Scheffner,et al.  Interaction between ubiquitin–protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation , 1999, Nature Cell Biology.

[17]  Charles J. Sherr,et al.  Nucleolar Arf sequesters Mdm2 and activates p53 , 1999, Nature Cell Biology.

[18]  Y Taya,et al.  A role for ATR in the DNA damage-induced phosphorylation of p53. , 1999, Genes & development.

[19]  W. Krek,et al.  Increased levels of E2F-1-dependent DNA binding activity after UV- or γ-irradiation , 1999 .

[20]  W. Krek,et al.  Increased levels of E2F-1-dependent DNA binding activity after UV- or gamma-irradiation. , 1999, Nucleic acids research.

[21]  W. El-Deiry,et al.  p53-independent increase in E2F-1 expression enhances the cytotoxic effects of etoposide and of adriamycin. , 1999, International journal of oncology.

[22]  Y Taya,et al.  Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. , 1998, Science.

[23]  Karen H. Vousden,et al.  p14ARF links the tumour suppressors RB and p53 , 1998, Nature.

[24]  K. Tsai,et al.  Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. , 1998, Molecular cell.

[25]  N. Dyson,et al.  Key roles for E2F1 in signaling p53-dependent apoptosis and in cell division within developing tumors. , 1998, Molecular cell.

[26]  J. Nevins,et al.  Toward an understanding of the functional complexity of the E2F and retinoblastoma families. , 1998, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[27]  N. Dyson.  The regulation of E2F by pRB-family proteins. , 1998, Genes & development.

[28]  J. Nevins,et al.  E2F3 activity is regulated during the cell cycle and is required for the induction of S phase. , 1998, Genes & development.

[29]  T. Jacks,et al.  Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/−) mice , 1998, Nature Genetics.

[30]  J. Wang,et al.  The caspase-RB connection in cell death. , 1998, Trends in cell biology.

[31]  J. Nevins,et al.  E2F1-specific induction of apoptosis and p53 accumulation, which is blocked by Mdm2. , 1998, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[32]  Hirofumi Tanaka,et al.  Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53 , 1997, FEBS letters.

[33]  Richard A. Ashmun,et al.  Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19 ARF , 1997, Cell.

[34]  Z. Yuan,et al.  Role for E2F in DNA damage-induced entry of cells into S phase. , 1997, Cancer research.

[35]  K. Helin,et al.  Induction of DNA synthesis and apoptosis are separable functions of E2F-1. , 1997, Genes & development.

[36]  J. Nevins,et al.  Distinct roles for E2F proteins in cell growth control and apoptosis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[37]  D. Livingston,et al.  The retinoblastoma gene product protects E2F-1 from degradation by the ubiquitin-proteasome pathway. , 1996, Genes & development.

[38]  A. Shvarts,et al.  Degradation of E2F by the ubiquitin-proteasome pathway: regulation by retinoblastoma family proteins and adenovirus transforming proteins. , 1996, Genes & development.

[39]  M. Greenberg,et al.  E2F-1 Functions in Mice to Promote Apoptosis and Suppress Proliferation , 1996, Cell.

[40]  W. Sellers,et al.  A potent transrepression domain in the retinoblastoma protein induces a cell cycle arrest when bound to E2F sites. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J. Nevins,et al.  E2F1 overexpression in quiescent fibroblasts leads to induction of cellular DNA synthesis and apoptosis , 1995, Journal of virology.

[42]  W. Lee,et al.  Deregulated expression of E2F-1 induces S-phase entry and leads to apoptosis , 1994, Molecular and cellular biology.

[43]  W. Kaelin,et al.  Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Wilhelm Krek,et al.  Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase , 1994, Cell.

[45]  P. Farnham,et al.  Multiple DNA elements are required for the growth regulation of the mouse E2F1 promoter. , 1994, Genes & development.

[46]  J. Nevins,et al.  Autoregulatory control of E2F1 expression in response to positive and negative regulators of cell cycle progression. , 1994, Genes & development.

[47]  A. Levine,et al.  p53 and E2F-1 cooperate to mediate apoptosis. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[48]  J. Nevins,et al.  Expression of transcription factor E2F1 induces quiescent cells to enter S phase , 1993, Nature.

[49]  Scott W. Lowe,et al.  p53 is required for radiation-induced apoptosis in mouse thymocytes , 1993, Nature.

[50]  C. Purdie,et al.  Thymocyte apoptosis induced by p53-dependent and independent pathways , 1993, Nature.

[51]  B. Vogelstein,et al.  A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia , 1992, Cell.

[52]  A. Bradley,et al.  Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis , 1992, Nature.

[53]  R. Weinberg,et al.  Effects of an Rb mutation in the mouse , 1992, Nature.

[54]  T. Halazonetis,et al.  Chk 2 / hCds 1 functions as a DNA damage checkpoint in G 1 by stabilizing p 53 , 2022 .

[55]  A. Levine,et al.  p 53 and E 2 F-1 cooperate to mediate apoptosis , 2022 .