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Published on: August 4, 2019

Trp53 regulates Notch 4 signaling through Mdm2

Youping Sun1, Malgorzata Klauzinska, Robert J Lake

  • 1Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.

Journal of Cell Science
|March 16, 2011
PubMed

Insights

The tumor suppressor Trp53 antagonizes Notch 4 signaling by promoting its degradation via Mdm2. This interaction suppresses Notch-driven mammary gland tumorigenesis.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Signaling

Background:

  • Notch receptors and ligands are key regulators in development and cancer.
  • Dysregulation of Notch signaling contributes to tumorigenesis.

Purpose of the Study:

  • To investigate the relationship between Notch 4 and the tumor suppressor Trp53.
  • To elucidate the mechanism controlling Notch 4 activity.

Main Methods:

  • Co-immunoprecipitation assays to detect protein interactions.
  • Ubiquitylation and degradation assays.
  • Cellular assays for anchorage-independent growth.
  • In vivo mammary gland tumor suppression studies.

Main Results:

  • Demonstrated an antagonistic relationship between Notch 4 and Trp53.
  • Identified Mdm2 as the E3 ligase mediating Notch 4 degradation.
  • Showed physical interaction between Mdm2 and Notch 4, forming a trimeric complex with Trp53.
  • Trp53 suppressed NICD4-induced anchorage-independent growth in mammary cells.

Conclusions:

  • Trp53 antagonizes Notch 4 activity through Mdm2-dependent degradation.
  • This pathway is critical for suppressing Notch-associated mammary gland tumorigenesis.

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