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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

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

Published on: August 4, 2019

p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2

S Cuenin1, A Tinel, S Janssens

  • 1Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.

Oncogene
|July 20, 2007
PubMed

Insights

A newly discovered third isoform of p53-induced protein with a death domain (PIDD) regulates cell fate following DNA damage. Differential splicing of PIDD mRNA creates isoforms with opposing functions, impacting cancer therapy and oncogenesis.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Cellular response to DNA damage is critical for preventing oncogenesis and is targeted in cancer therapies.
  • The p53-induced protein with a death domain (PIDD) acts as a molecular switch, influencing cell survival or apoptosis.
  • Two PIDD isoforms, PIDD (isoform 1) and LRDD (isoform 2), were previously identified.

Purpose of the Study:

  • To identify and characterize a third isoform of PIDD.
  • To investigate the differential expression and function of PIDD isoforms in response to genotoxic stress.
  • To elucidate the role of PIDD isoforms in regulating cell fate and apoptosis.

Main Methods:

  • Analysis of PIDD mRNA and protein expression across different tissues and cell lines.
  • Investigation of PIDD isoform interactions with key signaling molecules like RIPK1 and caspase-2.
  • Assessment of nuclear factor-kappaB (NF-κB) activation by PIDD isoforms.
  • Evaluation of the impact of PIDD isoforms on apoptosis induction.

Main Results:

  • A third PIDD isoform (isoform 3) was identified, exhibiting distinct mRNA expression patterns under genotoxic stress compared to isoforms 1 and 2.
  • All three PIDD isoforms activate NF-κB in response to genotoxic stress.
  • Only PIDD isoform 1 interacts with RIPK1 and activates caspase-2, initiating apoptosis.
  • PIDD isoform 2 antagonizes the pro-apoptotic function of isoform 1, while isoform 3 enhances it.

Conclusions:

  • Differential splicing of PIDD mRNA generates at least three protein isoforms with opposing regulatory functions.
  • These PIDD isoforms play a crucial role in modulating cell fate decisions in response to DNA damage.
  • The complex interplay of PIDD isoforms offers potential therapeutic targets for cancer treatment.

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