Role of the E-3 ligase CHIP in the negative regulation of the transcription factor TAp63

• Author / Creator

  Armstrong, Stephen, R.

• The p53 family of tumor suppressors is an important group of transcription factors preventing the development of cancer by targeting cell-cycle arrest and apoptosis mediator proteins for transcription. The most studied, p53, is frequently inactivated in carcinomas by mutation or genetic silencing, while the other two members TAp63 (transactivation domain containing p63) and TAp73 are rarely mutated, but rather are regulated at the protein level. The most common regulation method for TAp63 is post-translational modification, and one of the most prominent ways to negatively regulate expression and function of TAp63 is by ubiquitination followed by proteasome-mediated degradation. Ubiquitination of TAp63 is carried out by an E-3 ligase enzyme that is able to catalyze the attachment of a small peptide called ubiquitin to a target substrate. Poly-ubiquitin chains are required in order for the proteasome to recognize a substrate, and there are many E-3 ligases that can catalyze the attachment of poly-ubiquitin chains to the TAp63 protein. These include the primary regulator of TAp63, Itch/AIP4. In this study, we identify and characterize another primary regulator of TAp63, the E-3 ligase CHIP, which is a key mediator of ubiquitination during the heat shock response. We observed that CHIP is able to bind to TAp63, facilitating the attachment of polyubiquitin chains. The over-expression of CHIP in carcinoma cells results in a reduction in TAp63 protein expression, accompanied by oncogenic effects including an increase in cell survival, and a decrease in apoptosis and cell cycle arrest. Knockdown of endogenous CHIP results in an increase in TAp63 expression accompanied by tumor suppressive effects including a decrease in cell survival and migration, and an increase in apoptosis and cell cycle arrest. CHIP expression is negatively correlated with TAp63 expression in various carcinoma cell lines, and invasive prostate carcinoma patient tissue samples. This research supports an oncogenic role for CHIP in the negative regulation of TAp63 expression and function, and provides a possible therapeutic target for carcinoma treatment in the future.

• Subjects / Keywords

  • TAp63
  • CHIP
  • Ubiquitination
  • Tumor suppressor
  • Protein degradation
  • P63

• Graduation date

  Fall 2016

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R37W67B33

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.