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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Activated p53 induces NF-kappaB DNA binding but suppresses its transcriptional activation

Keiko Kawauchi1, Keigo Araki, Kei Tobiume

  • 1Department of Molecular Oncology, Institute of Gerontology, Nippon Medical School, Kosugi-cho 1-396, Nakahara-ku, Kawasaki-shi, Kanagawa 211-8533, Japan.

Biochemical and Biophysical Research Communications
|May 15, 2008
PubMed

Insights

The tumor suppressor p53 suppresses the activity of NF-kappaB, a key factor in cancer development. Activated p53 inhibits NF-kappaB signaling pathways, offering a new strategy against oncogenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Nuclear factor-kappa B (NF-kappaB) is crucial in oncogenesis.
  • Loss of p53 function amplifies NF-kappaB activity, promoting cell transformation via glycolysis.
  • NF-kappaB activation is linked to oncogene-induced cell transformation.

Purpose of the Study:

  • To investigate the mechanism by which activated p53 modulates NF-kappaB transcriptional activity.
  • To elucidate the role of p53 in regulating NF-kappaB signaling components like p65, IKKalpha, and IKKbeta.
  • To explore the potential of p53-mediated suppression of NF-kappaB as an anti-cancer strategy.

Main Methods:

  • Ectopic expression of p53 in cells.
  • Analysis of p65 acetylation and phosphorylation at Ser 536.
  • Assessment of NF-kappaB DNA-binding and transcriptional activities.
  • Co-immunoprecipitation to study protein complex formation (p65, IKKalpha, IKKbeta, p53).
  • Measurement of histone H3 kinase activity.

Main Results:

  • Activated p53 induces p65 acetylation and phosphorylation, enhancing its DNA-binding activity.
  • Despite enhanced DNA binding, activated p53 suppresses NF-kappaB transcriptional activity.
  • p53 disrupts the interaction between p65 and IKKbeta.
  • p53 diminishes histone H3 kinase activity, which is essential for NF-kappaB transcriptional activation.
  • Activated p53 inhibits NF-kappaB signaling by interfering with IKK and histone H3 kinase on DNA.

Conclusions:

  • Activated p53 suppresses NF-kappaB transcriptional activity through inhibition of IKK and histone H3 kinase.
  • This p53-mediated suppression mechanism offers a novel pathway to inhibit tumorigenesis.
  • Understanding this interaction could lead to new therapeutic strategies targeting NF-kappaB in cancer.

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