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

Published on: August 4, 2019

The Alzheimer's disease-associated TREM2 gene is regulated by p53 tumor suppressor protein

Artur Zajkowicz1, Agnieszka Gdowicz-Kłosok1, Małgorzata Krześniak1

  • 1Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie Institute-Oncology Center, Gliwice Branch, 44-101 Gliwice, Poland.

Neuroscience Letters
|May 30, 2018
PubMed

Insights

The study reveals that TREM2 is a direct target gene of p53. This discovery sheds light on the p53-dependent regulation of TREM2 and its pathway, potentially impacting neurodegenerative disorders like Alzheimer's disease.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • TREM2 mutations are linked to neurodegenerative disorders and increased Alzheimer's disease risk.
  • The TREM2 signaling pathway involves TYROBP, BLNK, and SYK, with p53 potentially regulating this cascade.
  • A putative p53 response element (RE) in the TREM2 promoter suggests p53-dependent regulation.

Purpose of the Study:

  • To investigate if TREM2 and its associated pathway genes are regulated by p53.
  • To confirm the functional role of the identified p53 RE in the TREM2 promoter.
  • To elucidate the mechanism of p53-mediated TREM2 activation.

Main Methods:

  • Stimulation of p53 using actinomycin D and nutlin-3a (A+N) in lung cancer cells (A549).
  • Analysis of TREM2, TYROBP, SYK, and BLNK expression in various cell lines (A549, U-2 OS, A375).
  • In vitro mutagenesis, chromatin immunoprecipitation, and luciferase reporter assays to validate p53 RE function.
  • Inhibition studies using glycogen synthase kinase-3 (GSK-3) inhibitor CHIR-98014.

Main Results:

  • Exposure to A+N induced TREM2, TYROBP, SYK, and BLNK expression in a p53-dependent manner in A549 cells.
  • TREM2 activation by A+N was observed in osteosarcoma (U-2 OS) and melanoma (A375) cells.
  • Nutlin-3a alone stimulated TREM2 in U-2 OS cells, confirming p53's role.
  • The p53 RE was confirmed in the TREM2 promoter, demonstrating direct p53 binding.
  • p53-mediated activation of TREM2 and TYROBP was significantly inhibited by GSK-3 inhibitor CHIR-98014.

Conclusions:

  • TREM2 is identified as a direct p53-target gene.
  • The activation of TREM2 by p53 activators (A+N or nutlin-3a) is critically dependent on glycogen synthase kinase-3 (GSK-3) function.
  • These findings provide new insights into the molecular mechanisms regulating TREM2 and its potential role in disease.
Keywords:
Actinomycin DAlzheimer's diseaseNutlin-3aTREM2p53

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