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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 Plays an important role in cell fate determination after exposure to microcystin-LR

Shota Takumi1, Masaharu Komatsu, Tatsuhiko Furukawa

  • 1Department of Environmental Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.

Environmental Health Perspectives
|April 28, 2010
PubMed
Abstract

Insights

The transcription factor p53 regulates cell fate after microcystin-LR exposure. Inactivation of p53 may promote cell proliferation, suggesting new approaches for treating microcystin-LR poisoning.

Area of Science:

  • Toxicology
  • Cell Biology
  • Molecular Biology

Background:

  • Microcystin-LR inhibits protein phosphatases PP1 and PP2A, causing liver toxicity and promoting tumor growth.
  • The mechanisms balancing cell death and proliferation following microcystin-LR exposure are not fully understood.

Purpose of the Study:

  • To investigate the roles of the transcription factor p53 and the uptake transporter OATP1B3 in cellular responses to microcystin-LR.
  • To elucidate how p53 influences cell fate decisions after microcystin-LR exposure.

Main Methods:

  • Utilized HEK293 cells stably expressing OATP1B3 (HEK293-OATP1B3) to analyze intracellular signaling via immunoblotting and RT-PCR.
  • Assessed microcystin-LR cytotoxicity by inhibiting p53 function with pifithrin-alpha and using p53 mRNA knockdown.

Main Results:

  • Microcystin-LR induced p53 phosphorylation and accumulation, upregulating p53 target genes (p21, siah-1) and activating Akt signaling.
  • Despite Akt activation, p53 accumulation induced apoptosis in HEK293-OATP1B3 cells after 24-hour exposure to 50 nM microcystin-LR.
  • Inhibition or knockdown of p53 attenuated microcystin-LR-induced cytotoxicity.

Conclusions:

  • p53 plays a critical role in determining cell fate after microcystin-LR exposure.
  • Inactivated p53 may lead to microcystin-LR-induced cell proliferation via Akt signaling, particularly with chronic low-dose exposure.
  • Findings may inform chemoprevention and chemotherapeutic strategies for microcystin-LR poisoning.

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