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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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Oncogene-mediated regulation of p53 ISGylation and functions

Yi-Fu Huang1, Dmitry V Bulavin2

  • 1Institute of Molecular and Cell Biology, Proteos, Singapore.

Oncotarget
|July 30, 2014
PubMed

Insights

Oncogenes enhance the stability of the p53 tumor suppressor through ISGylation. Blocking this process boosts p53

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Oncogene activation and tumor suppressor inactivation drive cellular transformation.
  • ISGylation (ISGylation) of p53 is a novel mechanism regulating its stability.
  • Oncogenes can modulate p53 ISGylation.

Purpose of the Study:

  • To investigate how oncogenes enhance p53 ISGylation.
  • To determine the functional consequences of Isg15-dependent p53 regulation in cancer.
  • To explore the therapeutic potential of targeting this pathway.

Main Methods:

  • Investigated Src-mediated phosphorylation of p53.
  • Assessed the effect of phosphorylation on Herc5 binding and p53 ISGylation.
  • Utilized Isg15-deficient cell and mouse models.
  • Evaluated p53 accumulation, activation, and anti-cancer activity.

Main Results:

  • Src-mediated phosphorylation of p53 at Tyr126 and Tyr220 enhances p53 ISGylation by increasing Herc5 binding.
  • Loss of Isg15 leads to p53 accumulation and activation in transformed cells.
  • Isg15 deletion suppresses tumorigenesis in mice by enhancing p53's anti-cancer activity.

Conclusions:

  • Isg15-dependent degradation of p53 represents an alternative oncogenic pathway to control p53 activity.
  • Targeting the Isg15-p53 interaction is a promising strategy for novel anti-cancer drug development.

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