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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

The involvement of MAPK signaling pathways in determining the cellular response to p53 activation: cell cycle arrest

Lauren Brown1, Samuel Benchimol

  • 1Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Canada.

The Journal of Biological Chemistry
|December 7, 2005
PubMed

Insights

Mitogen-activated protein kinases (MAPKs) like ERK, p38, and JNK impact p53-dependent apoptosis and cell cycle arrest in transformed cells. Their activity can promote or inhibit these processes, influencing cancer therapy effectiveness.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Friend murine erythroleukemia virus (FVP)-transformed cells (DP16.1/p53ts) exhibit temperature-sensitive p53, enabling p53-dependent G1 cell cycle arrest and apoptosis upon activation.
  • Viral transformation leads to expression of gp55, a protein that binds the erythropoietin receptor (EPO-R) and mimics EPO signaling.

Purpose of the Study:

  • To investigate the role of ERK, p38, and JNK signaling pathways in mediating p53-dependent apoptosis and cell cycle arrest.
  • To elucidate how constitutive mitogen-activated protein kinase (MAPK) activity in transformed cells influences the p53 pathway.

Main Methods:

  • Utilized a DP16.1/p53ts cell line with temperature-sensitive p53.
  • Analyzed the constitutive activity of ERK, p38, and JNK MAPKs.
  • Investigated the effects of MEK inhibition on p53-dependent cellular responses and p21(WAF1) expression.
  • Assessed the impact of p38 and JNK inhibition on apoptosis and p53 protein turnover.

Main Results:

  • Constitutive MEK activity promotes p53-dependent apoptosis and p53 phosphorylation at serine 15, potentially due to aberrant Ras signaling.
  • MEK inhibition shifts the cellular response from apoptosis to G1 cell cycle arrest, increasing p21(WAF1) levels.
  • p38 and JNK signaling exhibit anti-apoptotic effects, limiting p53-dependent apoptosis.
  • JNK activity promotes p53 protein turnover, and its inhibition enhances apoptosis.

Conclusions:

  • Intrinsic MAPK pathways in transformed cells exert both positive and negative regulation on p53-dependent apoptosis.
  • Aberrant Ras/MEK signaling contributes to apoptosis, while p38/JNK signaling acts as a brake on apoptosis.
  • Understanding these MAPK influences is crucial for developing cancer therapies that target p53 function.

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