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14:57
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Activating transcription factor 3 activates p53 by preventing E6-associated protein from binding to E6
Hongbo Wang1, Pingli Mo, Shumei Ren
1Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208, USA.
The Journal of Biological Chemistry
|February 20, 2010
Summary
Activating transcription factor 3 (ATF3) prevents human papillomavirus (HPV) E6 protein from degrading the tumor suppressor p53. This finding reveals ATF3 as a potential therapeutic target for HPV-driven cervical cancers.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Human papillomavirus (HPV) DNA integration causes over 90% of cervical cancers.
- HPV E6 proteins target the tumor suppressor p53 for degradation via E6-associated protein (E6AP).
- Regulation of this critical p53 degradation pathway remains largely unknown.
Purpose of the Study:
- To investigate the regulatory mechanisms of p53 degradation induced by HPV E6.
- To identify potential cellular factors that counteract HPV-induced p53 loss in cervical cancer.
Main Methods:
- Co-immunoprecipitation assays to detect protein interactions.
- Western blotting to assess protein levels and ubiquitination.
- Expression of ATF3 in HPV-positive cervical cancer cells (SiHa).
- Analysis of p53-target gene expression and cellular phenotypes (cell cycle arrest, apoptosis).
Main Results:
- Activating transcription factor 3 (ATF3) interacts with HPV E6.
- ATF3 prevents E6-mediated ubiquitination and degradation of p53.
- ATF3 disrupts the interaction between HPV E6 and E6AP.
- Enforced ATF3 expression in HPV-positive cells restores p53 levels, induces p53-target genes (p21, PUMA), causes cell cycle arrest, and promotes apoptosis.
- The leucine zipper domain of ATF3 is crucial for its interaction with E6 and subsequent p53 stabilization.
Conclusions:
- ATF3 acts as a potent antagonist of HPV E6, protecting p53 from degradation.
- ATF3 plays a significant role in defending against HPV-induced cervical carcinogenesis.
- ATF3 represents a novel therapeutic target for HPV-positive cancers.
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