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The ubiquitin-protein ligase Itch regulates p73 stability

Mario Rossi1, Vincenzo De Laurenzi, Eliana Munarriz

  • 1Department of Biology, University of Rome Tor Vergata, Rome, Italy.

The EMBO Journal
|January 29, 2005
PubMed

Insights

The Itch ubiquitin ligase targets the p73 protein for degradation, controlling its levels. DNA damage downregulates Itch, allowing p73 to accumulate and influence cellular responses.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The p73 protein, part of the p53 family, is crucial for DNA damage response, inducing cell cycle arrest and apoptosis.
  • While p73's response to DNA damage is known to be post-transcriptional, the mechanisms regulating p73 protein degradation remain largely uncharacterized.
  • Unlike p53, which is degraded by MDM2, p73's degradation pathway is not well understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms governing p73 protein degradation.
  • To identify proteins that regulate p73 stability and degradation.
  • To understand how p73 protein levels are controlled under normal and stress conditions.

Main Methods:

  • Investigated the interaction between p73 and the Hect ubiquitin-protein ligase, Itch.
  • Utilized ubiquitination assays to determine Itch's effect on p73.
  • Examined the impact of DNA damage on Itch expression levels.

Main Results:

  • Identified Itch as a Hect ubiquitin-protein ligase that selectively binds and ubiquitinates p73.
  • Demonstrated that Itch-mediated ubiquitination leads to rapid, proteasome-dependent degradation of p73.
  • Showed that Itch expression is downregulated upon DNA damage, leading to an increase in p73 protein levels.

Conclusions:

  • Discovered a novel mechanism controlling p73 protein levels through Itch-mediated degradation.
  • Established Itch as a key regulator of p73 stability in both normal and stress conditions.
  • Highlighted the dynamic regulation of p73 by Itch, impacting its function during DNA damage response.

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