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Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
Notch Signaling Pathway03:14

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The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
Notch Signaling Pathway03:14

Notch Signaling Pathway

The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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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
Summary

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

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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.