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PMID: 15024084 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Apoptosis associated with deregulated E2F activity is dependent on E2F1 and Atm/Nbs1/Chk2.

Molecular and cellular biology ·Vol. 24 ·No. 7 ·2004-04-00 ·Pages 2968-77

Rogoff HA, Pickering MT, Frame FM, Debatis ME, Sanchez Y, Jones S, Kowalik TF

Abstract

The retinoblastoma protein (Rb)/E2F pathway links cellular proliferation control to apoptosis and is critical for normal development and cancer prevention. Here we define a transcription-mediated pathway in which deregulation of E2F1 by ectopic E2F expression or Rb inactivation by E7 of human papillomavirus type 16 signals apoptosis by inducing the expression of Chk2, a component of the DNA damage response. E2F1- and E7-mediated apoptosis are compromised in cells from patients with the related disorders ataxia telangiectasia and Nijmegen breakage syndrome lacking functional Atm and Nbs1 gene products, respectively. Both Atm and Nbs1 contribute to Chk2 activation and p53 phosphorylation following deregulation of normal Rb growth control. E2F2, a related E2F family member that does not induce apoptosis, also activates Atm, resulting in phosphorylation of p53. However, we found that the key commitment step in apoptosis induction is the ability of E2F1, and not E2F2, to upregulate Chk2 expression. Our results suggest that E2F1 plays a central role in signaling disturbances in the Rb growth control pathway and, by upregulation of Chk2, may sensitize cells to undergo apoptosis.

MeSH Terms
Animals Apoptosis/physiology Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins/metabolism Cells, Cultured Checkpoint Kinase 2 DNA-Binding Proteins E2F Transcription Factors E2F1 Transcription Factor E2F2 Transcription Factor Fibroblasts/cytology,physiology Gene Expression Regulation Humans Mice Mice, Transgenic Nuclear Proteins/metabolism Oncogene Proteins, Viral/metabolism Papillomavirus E7 Proteins Protein Serine-Threonine Kinases/metabolism Retinoblastoma Protein/metabolism Signal Transduction/physiology Transcription Factors/metabolism Tumor Suppressor Protein p53/metabolism Tumor Suppressor Proteins
Chemicals
Cell Cycle Proteins DNA-Binding Proteins E2F Transcription Factors E2F1 Transcription Factor E2F1 protein, human E2F2 Transcription Factor E2F2 protein, human E2f1 protein, mouse NBN protein, human Nuclear Proteins Oncogene Proteins, Viral Papillomavirus E7 Proteins Retinoblastoma Protein Transcription Factors Tumor Suppressor Protein p53 Tumor Suppressor Proteins oncogene protein E7, Human papillomavirus type 16 Checkpoint Kinase 2 ATM protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse CHEK2 protein, human Chek2 protein, mouse Protein Serine-Threonine Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Rogoff Harry A
Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Pickering Mary T
Frame Fiona M
Debatis Michelle E
Sanchez Yolanda
Jones Stephen
Kowalik Timothy F
References (90)
90 references, click to expand
  1. Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system.
    EMBO J. 1996 Nov 15;15(22):6178-88 PMID: 8947040
  2. Mdm2 promotes the rapid degradation of p53.
    Nature. 1997 May 15;387(6630):296-9 PMID: 9153395
  3. Distinct roles for E2F proteins in cell growth control and apoptosis.
    Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7245-50 PMID: 9207076
  4. Role for E2F in DNA damage-induced entry of cells into S phase.
    Cancer Res. 1997 Sep 1;57(17):3640-3 PMID: 9288762
  5. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF.
    Cell. 1997 Nov 28;91(5):649-59 PMID: 9393858
  6. Atm selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways.
    Nat Genet. 1997 Dec;17(4):453-6 PMID: 9398849
  7. DNA damage induces phosphorylation of the amino terminus of p53.
    Genes Dev. 1997 Dec 15;11(24):3471-81 PMID: 9407038
  8. The p53 network.
    J Biol Chem. 1998 Jan 2;273(1):1-4 PMID: 9417035
  9. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53.
    FEBS Lett. 1997 Dec 22;420(1):25-7 PMID: 9450543
  10. E2F1-specific induction of apoptosis and p53 accumulation, which is blocked by Mdm2.
    Cell Growth Differ. 1998 Feb;9(2):113-8 PMID: 9486847
  11. A simplified system for generating recombinant adenoviruses.
    Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2509-14 PMID: 9482916
  12. Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system.
    Science. 1998 May 15;280(5366):1089-91 PMID: 9582124
  13. Increased E2F1 activity induces skin tumors in mice heterozygous and nullizygous for p53.
    Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8858-63 PMID: 9671769
  14. Toward an understanding of the functional complexity of the E2F and retinoblastoma families.
    Cell Growth Differ. 1998 Aug;9(8):585-93 PMID: 9716176
  15. Enhanced phosphorylation of p53 by ATM in response to DNA damage.
    Science. 1998 Sep 11;281(5383):1674-7 PMID: 9733514
  16. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.
    Science. 1998 Sep 11;281(5383):1677-9 PMID: 9733515
  17. p14ARF links the tumour suppressors RB and p53.
    Nature. 1998 Sep 10;395(6698):124-5 PMID: 9744267
  18. The complexity of p53 modulation: emerging patterns from divergent signals.
    Genes Dev. 1998 Oct 1;12(19):2973-83 PMID: 9765199
  19. Key roles for E2F1 in signaling p53-dependent apoptosis and in cell division within developing tumors.
    Mol Cell. 1998 Sep;2(3):283-92 PMID: 9774967
  20. Signaling to p53: breaking the MDM2-p53 circuit.
    Cell. 1998 Oct 2;95(1):5-8 PMID: 9778240
  21. The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53.
    Mol Cell Biol. 1998 Nov;18(11):6457-73 PMID: 9774662
  22. Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6.
    Mol Cell Biol. 1998 Dec;18(12):7288-93 PMID: 9819415
  23. Mdm2 association with p53 targets its ubiquitination.
    Oncogene. 1998 Nov 12;17(19):2543-7 PMID: 9824166
  24. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.
    Science. 1998 Dec 4;282(5395):1893-7 PMID: 9836640
  25. Increased levels of E2F-1-dependent DNA binding activity after UV- or gamma-irradiation.
    Nucleic Acids Res. 1999 Jan 15;27(2):491-5 PMID: 9862970
  26. p53-independent increase in E2F-1 expression enhances the cytotoxic effects of etoposide and of adriamycin.
    Int J Oncol. 1999 Jan;14(1):5-14 PMID: 9863003
  27. Chk2 is dispensable for p53-mediated G1 arrest but is required for a latent p53-mediated apoptotic response.
    Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):9825-9 PMID: 12097646
  28. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription.
    EMBO J. 2002 Oct 1;21(19):5195-205 PMID: 12356735
  29. Direct coupling of the cell cycle and cell death machinery by E2F.
    Nat Cell Biol. 2002 Nov;4(11):859-64 PMID: 12389032
  30. The human papillomavirus type 16 E6 and E7 oncoproteins independently induce numerical and structural chromosome instability.
    Cancer Res. 2002 Dec 1;62(23):7075-82 PMID: 12460929
  31. Checkpoint kinase 2 (Chk2) monomers or dimers phosphorylate Cdc25C after DNA damage regardless of threonine 68 phosphorylation.
    J Biol Chem. 2002 Dec 13;277(50):48418-26 PMID: 12386164
  32. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.
    Nature. 2003 Jan 30;421(6922):499-506 PMID: 12556884
  33. Chk2 activates E2F-1 in response to DNA damage.
    Nat Cell Biol. 2003 May;5(5):401-9 PMID: 12717439
  34. Regulation of the Chk2 protein kinase by oligomerization-mediated cis- and trans-phosphorylation.
    Mol Cancer Res. 2003 Jun;1(8):598-609 PMID: 12805407
  35. Autophosphorylation of checkpoint kinase 2 at serine 516 is required for radiation-induced apoptosis.
    J Biol Chem. 2003 Sep 19;278(38):36163-8 PMID: 12855706
  36. Human papillomavirus type 16 E7 regulates E2F and contributes to mitogenic signalling.
    Oncogene. 1993 Apr;8(4):893-8 PMID: 8455943
  37. Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B.
    Genes Dev. 1993 Apr;7(4):546-54 PMID: 8384580
  38. Expression of transcription factor E2F1 induces quiescent cells to enter S phase.
    Nature. 1993 Sep 23;365(6444):349-52 PMID: 8377827
  39. p53 and E2F-1 cooperate to mediate apoptosis.
    Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3602-6 PMID: 8170954
  40. Atm is dispensable for p53 apoptosis and tumor suppression triggered by cell cycle dysfunction.
    Mol Cell Biol. 1999 Apr;19(4):3095-102 PMID: 10082576
  41. A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage.
    Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3745-50 PMID: 10097108
  42. Induction of ARF tumor suppressor gene expression and cell cycle arrest by transcription factor DMP1.
    Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3993-8 PMID: 10097151
  43. Transcription factor E2F-1 is upregulated in response to DNA damage in a manner analogous to that of p53.
    Mol Cell Biol. 1999 May;19(5):3704-13 PMID: 10207094
  44. Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway.
    Oncogene. 1999 Jul 15;18(28):4047-54 PMID: 10435585
  45. The ataxia-telangiectasia related protein ATR mediates DNA-dependent phosphorylation of p53.
    Oncogene. 1999 Jul 8;18(27):3989-95 PMID: 10435622
  46. ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK.
    Oncogene. 1999 Nov 18;18(48):6707-13 PMID: 10597277
  47. Substrate specificities and identification of putative substrates of ATM kinase family members.
    J Biol Chem. 1999 Dec 31;274(53):37538-43 PMID: 10608806
  48. The E2F transcription factors: key regulators of cell proliferation.
    Biochim Biophys Acta. 2000 Feb 14;1470(1):M1-12 PMID: 10656985
  49. Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53.
    Genes Dev. 2000 Feb 1;14(3):278-88 PMID: 10673500
  50. The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites.
    Genes Dev. 2000 Feb 1;14(3):289-300 PMID: 10673501
  51. ATR disruption leads to chromosomal fragmentation and early embryonic lethality.
    Genes Dev. 2000 Feb 15;14(4):397-402 PMID: 10691732
  52. DNA damage-induced activation of p53 by the checkpoint kinase Chk2.
    Science. 2000 Mar 10;287(5459):1824-7 PMID: 10710310
  53. ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway.
    Nature. 2000 Apr 6;404(6778):613-7 PMID: 10766245
  54. Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice.
    Curr Biol. 2000 Apr 20;10(8):479-82 PMID: 10801416
  55. Stress signals induce transcriptionally inactive E2F-1 independently of p53 and Rb.
    Oncogene. 2000 May 11;19(20):2369-76 PMID: 10828878
  56. Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products.
    Nature. 2000 May 25;405(6785):473-7 PMID: 10839544
  57. Role of human cytomegalovirus immediate-early proteins in cell growth control.
    J Virol. 2000 Sep;74(17):8028-37 PMID: 10933712
  58. Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro.
    Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10389-94 PMID: 10973490
  59. The Rb/E2F pathway: expanding roles and emerging paradigms.
    Genes Dev. 2000 Oct 1;14(19):2393-409 PMID: 11018009
  60. Threonine 68 is required for radiation-induced phosphorylation and activation of Cds1.
    Nat Cell Biol. 2000 Oct;2(10):762-5 PMID: 11025670
  61. Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts.
    Genes Dev. 2000 Nov 1;14(21):2745-56 PMID: 11069891
  62. p53: death star.
    Cell. 2000 Nov 22;103(5):691-4 PMID: 11114324
  63. Xenopus ATR is a replication-dependent chromatin-binding protein required for the DNA replication checkpoint.
    Curr Biol. 2000 Dec 14-28;10(24):1565-73 PMID: 11137007
  64. ATM and ATR: networking cellular responses to DNA damage.
    Curr Opin Genet Dev. 2001 Feb;11(1):71-7 PMID: 11163154
  65. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis.
    Genes Dev. 2001 Feb 1;15(3):267-85 PMID: 11159908
  66. The many substrates and functions of ATM.
    Nat Rev Mol Cell Biol. 2000 Dec;1(3):179-86 PMID: 11252893
  67. Expression analysis using DNA microarrays demonstrates that E2F-1 up-regulates expression of DNA replication genes including replication protein A2.
    Oncogene. 2001 Mar 15;20(11):1379-87 PMID: 11313881
  68. Post-translational modifications and activation of p53 by genotoxic stresses.
    Eur J Biochem. 2001 May;268(10):2764-72 PMID: 11358490
  69. E2F-1 induced apoptosis.
    Apoptosis. 2001 Jun;6(3):173-82 PMID: 11388666
  70. Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis.
    Mol Cell Biol. 2001 Jul;21(14):4684-99 PMID: 11416145
  71. Chk2 activation dependence on Nbs1 after DNA damage.
    Mol Cell Biol. 2001 Aug;21(15):5214-22 PMID: 11438675
  72. Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation.
    Genes Dev. 2001 Jul 15;15(14):1833-44 PMID: 11459832
  73. ATR inhibition selectively sensitizes G1 checkpoint-deficient cells to lethal premature chromatin condensation.
    Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9092-7 PMID: 11481475
  74. Myc requires distinct E2F activities to induce S phase and apoptosis.
    Mol Cell. 2001 Jul;8(1):105-13 PMID: 11511364
  75. Cell cycle checkpoint signaling through the ATM and ATR kinases.
    Genes Dev. 2001 Sep 1;15(17):2177-96 PMID: 11544175
  76. Use of chromatin immunoprecipitation to clone novel E2F target promoters.
    Mol Cell Biol. 2001 Oct;21(20):6820-32 PMID: 11564866
  77. Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway.
    J Biol Chem. 2001 Nov 16;276(46):43305-12 PMID: 11551930
  78. The p53 functional circuit.
    J Cell Sci. 2001 Dec;114(Pt 23):4139-40 PMID: 11739646
  79. p19(ARF) is dispensable for oncogenic stress-induced p53-mediated apoptosis and tumor suppression in vivo.
    Mol Cell Biol. 2002 Jan;22(1):370-7 PMID: 11739748
  80. E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints.
    Genes Dev. 2002 Jan 15;16(2):245-56 PMID: 11799067
  81. ARF is not required for apoptosis in Rb mutant mouse embryos.
    Curr Biol. 2002 Jan 22;12(2):159-63 PMID: 11818069
  82. ARF differentially modulates apoptosis induced by E2F1 and Myc.
    Mol Cell Biol. 2002 Mar;22(5):1360-8 PMID: 11839803
  83. Identification of novel E2F1-regulated genes by microarray.
    Arch Biochem Biophys. 2002 Mar 15;399(2):212-24 PMID: 11888208
  84. Gene expression changes in response to E2F1 activation.
    Nucleic Acids Res. 2002 Apr 15;30(8):1859-67 PMID: 11937641
  85. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis.
    Mutat Res. 2002 Jun;511(2):145-78 PMID: 12052432
  86. E2F1 induces phosphorylation of p53 that is coincident with p53 accumulation and apoptosis.
    Mol Cell Biol. 2002 Aug;22(15):5308-18 PMID: 12101227
  87. Mediation of c-Myc-induced apoptosis by p53.
    Science. 1994 Sep 30;265(5181):2091-3 PMID: 8091232
  88. Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis.
    Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10918-22 PMID: 7971984
  89. Expression of the E2F1 transcription factor overcomes type beta transforming growth factor-mediated growth suppression.
    Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):483-7 PMID: 7831315
  90. E2F1 overexpression in quiescent fibroblasts leads to induction of cellular DNA synthesis and apoptosis.
    J Virol. 1995 Apr;69(4):2491-500 PMID: 7884898
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.7.2968-2977.2004
Published
2004-04-00
Pages
2968-77
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC371110
Subset
IM
Grants
NCI NIH HHS · CA86038 · United States
NCI NIH HHS · R01 CA077735 · United States
NIAID NIH HHS · 5T32 AI07349 · United States
NCI NIH HHS · CA77735 · United States
NCI NIH HHS · R01 CA086038 · United States
NIAID NIH HHS · T32 AI007349 · United States
NCI NIH HHS · R56 CA077735 · United States
External Links
PubMed source DOI: 10.1128/MCB.24.7.2968-2977.2004 PMC Full Text View journal details
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