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GRIM-19 disrupts E6/E6AP complex to rescue p53 and induce apoptosis in cervical cancers

Ying Zhou1, Ying Wei, Jing Zhu

  • 1Department of Obstetrics and Gynecology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, Anhui, The People's Republic of China.

Plos One
|July 19, 2011
PubMed
Abstract

Insights

Restoring GRIM-19 in cervical cancer cells rescues tumor suppressor p53 by degrading E6AP. This disruption of the E6/E6AP complex inhibits cervical tumor growth and promotes apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Virology

Background:

  • GRIM-19 is downregulated in cervical cancers, and its restoration inhibits tumor growth.
  • High-risk HPV's E6 oncoprotein targets tumor suppressor p53 for degradation via E6AP, promoting cervical tumor development.

Purpose of the Study:

  • To investigate the role of GRIM-19 in preserving p53 protein levels.
  • To determine if GRIM-19 can induce apoptosis in cervical cancer cells.

Main Methods:

  • Compared GRIM-19 and p53 protein levels in normal and cancerous cervical tissues.
  • Utilized coimmunoprecipitation and GST pull-down assays to study GRIM-19 interactions with E6 and E6AP.
  • Assessed the impact of GRIM-19 on E6AP ubiquitination, p53 accumulation, cell proliferation, cell cycle, and apoptosis.
  • Evaluated tumor suppression in a xenograft mouse model.

Main Results:

  • GRIM-19 and p53 levels were concurrently downregulated in cervical cancers.
  • GRIM-19 interacts with E6 and E6AP, disrupting the E6/E6AP complex and preventing p53 degradation.
  • GRIM-19 restoration led to p53 accumulation, promoting cell apoptosis and inhibiting proliferation.
  • Xenograft studies confirmed GRIM-19's tumor suppressive effects.

Conclusions:

  • GRIM-19 restoration degrades E6AP, disrupting the E6/E6AP complex and stabilizing p53.
  • GRIM-19 protects p53 from degradation, induces cervical cancer cell apoptosis, and suppresses tumor growth.
  • GRIM-19 acts synergistically with p53 to inhibit cervical tumor progression.

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