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Enigma negatively regulates p53 through MDM2 and promotes tumor cell survival in mice

Cho-Rok Jung1, Jung Hwa Lim, Yoonjung Choi

  • 1Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea.

The Journal of Clinical Investigation
|November 10, 2010
PubMed

Insights

The LIM domain protein Enigma inhibits MDM2 self-ubiquitination, promoting p53 degradation. This pathway, regulated by mitogens and SRF, plays a role in tumorigenesis and chemoresistance.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Oncology

Background:

  • The E3 ubiquitin ligase MDM2 targets tumor suppressor p53 for degradation.
  • Maintaining the balance between MDM2 and p53 is critical for cell proliferation and apoptosis.
  • Factors inhibiting MDM2 self-ubiquitination are sought to understand cancer regulation.

Purpose of the Study:

  • Identify factors that selectively inhibit MDM2 self-ubiquitination.
  • Elucidate the role of Enigma in the MDM2/p53 pathway.
  • Investigate the link between Enigma, mitogenic stimuli, and tumorigenesis.

Main Methods:

  • In vitro and cell line studies using human hepatoma, colon carcinoma, and mouse embryonic fibroblasts.
  • Analysis of protein interactions and ubiquitination assays.
  • In vivo studies including mouse xenograft models and analysis of human tumor samples.

Main Results:

  • Enigma directly interacts with MDM2, forming a ternary complex with p53.
  • Enigma inhibits MDM2 self-ubiquitination and enhances MDM2's ligase activity toward p53.
  • Mitogenic stimuli (serum, FGF, HGF) induce Enigma transcription via SRF, leading to p53 degradation.
  • Enigma promotes cell survival and chemoresistance by suppressing p53-mediated apoptosis.
  • SRF and Enigma are coexpressed with MDM2 in human liver and stomach tumors.

Conclusions:

  • Enigma plays a role in tumorigenesis by modulating the MDM2/p53 pathway.
  • The SRF/Enigma/MDM2 pathway represents a mechanism by which mitogens reduce p53's antiproliferative activity.
  • Enigma's function in promoting cell survival and chemoresistance highlights its potential as a therapeutic target.

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