E2F1 uses the ATM signaling pathway to induce p53 and Chk2 phosphorylation and apoptosis

John T. Powers, SungKi Hong, Christopher N. Mayhew, Pamela M. Rogers, Erik S. Knudsen, David G. Johnson

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

The p53 tumor suppressor protein is phosphorylated and activated by several DNA damage-inducible kinases, such as ATM, and is a key effector of the DNA damage response by promoting cell cycle arrest or apoptosis. Deregulation of the Rb-E2F1 pathway also results in the activation of p53 and the promotion of apoptosis, and this contributes to the suppression of tumor development. Here, we describe a novel connection between E2F1 and the ATM DNA damage response pathway. In primary human fibroblasts lacking functional ATM, the ability of E2F1 to induce the phosphorylation of p53 and apoptosis is impaired. In contrast, ATM status has no effect on transcriptional activation of target genes or the stimulation of DNA synthesis by E2P1. Cells containing mutant Nijmegen breakage syndrome protein (NBS1), a component of the Mre11-Rad50 DNA repair complex, also have attenuated p53 phosphorylation and apoptosis in response to E2F1 expression. Moreover, E2F1 induces ATM- and NBS1-dependent phosphorylation of the checkpoint kinase Chk2 at Thr68, a phosphorylation site that stimulates Chk2 activity. Delayed γH2AX phosphorylation and absence of ATM autophosphorylation at Ser1981 suggest that E2F1 stimulates ATM through a unique mechanism that is distinct from agents that cause DNA double-strand breaks. These findings identify new roles for several DNA damage response factors by demonstrating that they also participate in the oncogenic stress signaling pathway between E2F1 and p53.

Original languageEnglish (US)
Pages (from-to)203-214
Number of pages12
JournalMolecular Cancer Research
Volume2
Issue number4
StatePublished - Apr 2004

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Phosphorylation
DNA Damage
Apoptosis
Phosphotransferases
Nijmegen Breakage Syndrome
Tumor Suppressor Protein p53
Double-Stranded DNA Breaks
Cell Cycle Checkpoints
DNA Repair
Transcriptional Activation
Fibroblasts
DNA
Genes
Neoplasms
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Powers, J. T., Hong, S., Mayhew, C. N., Rogers, P. M., Knudsen, E. S., & Johnson, D. G. (2004). E2F1 uses the ATM signaling pathway to induce p53 and Chk2 phosphorylation and apoptosis. Molecular Cancer Research, 2(4), 203-214.

E2F1 uses the ATM signaling pathway to induce p53 and Chk2 phosphorylation and apoptosis. / Powers, John T.; Hong, SungKi; Mayhew, Christopher N.; Rogers, Pamela M.; Knudsen, Erik S.; Johnson, David G.

In: Molecular Cancer Research, Vol. 2, No. 4, 04.2004, p. 203-214.

Research output: Contribution to journalArticle

Powers, JT, Hong, S, Mayhew, CN, Rogers, PM, Knudsen, ES & Johnson, DG 2004, 'E2F1 uses the ATM signaling pathway to induce p53 and Chk2 phosphorylation and apoptosis', Molecular Cancer Research, vol. 2, no. 4, pp. 203-214.
Powers JT, Hong S, Mayhew CN, Rogers PM, Knudsen ES, Johnson DG. E2F1 uses the ATM signaling pathway to induce p53 and Chk2 phosphorylation and apoptosis. Molecular Cancer Research. 2004 Apr;2(4):203-214.
Powers, John T. ; Hong, SungKi ; Mayhew, Christopher N. ; Rogers, Pamela M. ; Knudsen, Erik S. ; Johnson, David G. / E2F1 uses the ATM signaling pathway to induce p53 and Chk2 phosphorylation and apoptosis. In: Molecular Cancer Research. 2004 ; Vol. 2, No. 4. pp. 203-214.
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