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Cross-regulation of protein stability by p53 and nuclear receptor SHP

Zhihong Yang1, Yuxia Zhang, Jongsook Kim Kemper

  • 1Departments of Medicine and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.

Plos One
|June 28, 2012
PubMed

Insights

Tumor suppressors p53 and SHP (small heterodimer partner) cross-regulate each other's stability and function. This novel interplay impacts their tumor suppressor roles, particularly in colon cancer growth inhibition.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • The tumor suppressor p53 plays a critical role in preventing cancer.
  • The nuclear receptor SHP is involved in various metabolic and cellular processes.
  • Understanding the regulation of tumor suppressor stability is crucial for cancer therapy.

Purpose of the Study:

  • To investigate the novel interplay between tumor suppressor p53 and nuclear receptor SHP.
  • To elucidate the mechanisms controlling the stability of p53 and SHP.
  • To determine the impact of this cross-regulation on tumor suppressor functions in colon cancer.

Main Methods:

  • Protein expression and degradation assays.
  • Proteasome pathway inhibition.
  • Ubiquitin ligase activity assays.
  • Site-directed mutagenesis of SHP protein.
  • Colon cancer cell line studies.

Main Results:

  • Overexpression of p53 leads to proteasome-mediated degradation of SHP, independent of Mdm2.
  • SHP destabilizes p53 by enhancing Mdm2 ubiquitin ligase activity.
  • Specific mutations in SHP (SHPK170R, SHPG171A) alter its binding affinity to p53.
  • The cross-regulation between p53 and SHP compromises their tumor suppressor functions in colon cancer.

Conclusions:

  • A novel cross-inhibitory mechanism exists between tumor suppressors p53 and SHP.
  • This interplay regulates the stability and function of both proteins.
  • The findings reveal a unique regulatory network impacting colon cancer progression.

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