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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

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Regulation of TopBP1 oligomerization by Akt/PKB for cell survival

Kang Liu1, Jason C Paik, Bing Wang

  • 1Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

The EMBO Journal
|September 29, 2006
PubMed

Insights

Topoisomerase Binding Protein 1 (TopBP1) controls apoptosis by interacting with E2F1. The PI3K-Akt pathway phosphorylates TopBP1, inducing its oligomerization and repression of E2F1 proapoptotic activity.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Regulation of E2F1-mediated apoptosis is critical for cellular growth control.
  • Topoisomerase Binding Protein 1 (TopBP1), a BRCT domain protein, specifically interacts with E2F1 to repress its proapoptotic activity.
  • This regulation is known to be independent of pocket proteins.

Purpose of the Study:

  • To elucidate the mechanism by which TopBP1 regulates E2F1-mediated apoptosis.
  • To investigate the role of the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway in TopBP1-mediated control of E2F1.
  • To determine if TopBP1 oligomerization is essential for its interaction with and repression of E2F1.

Main Methods:

  • In vitro and in vivo Akt phosphorylation assays of TopBP1.
  • Analysis of TopBP1 oligomerization induced by Akt phosphorylation.
  • Co-immunoprecipitation assays to assess interactions between TopBP1, E2F1, Miz1, and HPV16 E2.
  • Reporter assays to measure Miz1 transcriptional activity.

Main Results:

  • Akt phosphorylates TopBP1 both in vitro and in vivo.
  • Akt-dependent phosphorylation induces TopBP1 oligomerization via its seventh and eighth BRCT domains.
  • Oligomerized TopBP1 is required for interaction with and repression of E2F1.
  • Akt phosphorylation is also necessary for TopBP1 interactions with Miz1 and HPV16 E2, and for repression of Miz1 activity.

Conclusions:

  • A novel pathway involving PI3K-Akt-TopBP1 is defined for the specific control of E2F1 apoptosis.
  • Akt-mediated phosphorylation and subsequent oligomerization of TopBP1 are crucial for repressing E2F1 proapoptotic activity.
  • TopBP1 oligomerization appears to play a general role in controlling transcription factors, including Miz1 and HPV16 E2.

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