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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

Attenuated p53 Expression and Lack of Effect of TGFalpha on Cell Replication in Enzyme Altered Foci

P Lennartsson1, U Stenius, J Högberg

  • 1Department of Occupational Toxicology, Institute of Environmental Health, Karolinska Institutet, Box 210, 171 Stockholm, Sweden.

Toxicology in Vitro : an International Journal Published in Association with BIBRA
|July 27, 2010
PubMed

Insights

Enzyme altered foci (EAF) in rat liver show a reduced p53 protein response to DNA-damaging agents. This suggests adaptive changes in EAF hepatocytes beyond altered metabolism.

Area of Science:

  • Hepatology
  • Carcinogenesis
  • Molecular Biology

Background:

  • Enzyme altered foci (EAF) are precarcinogenic lesions in rat liver associated with stress.
  • Previous in vitro studies suggested EAF hepatocytes do not accumulate p53 protein in response to DNA-damaging agents.

Purpose of the Study:

  • To investigate the in situ p53 protein response in EAF hepatocytes.
  • To compare the p53 response in EAF versus non-EAF hepatocytes.
  • To explore factors contributing to the attenuated p53 response in EAF.

Main Methods:

  • Immunohistochemistry to assess p53 protein accumulation in situ.
  • Treatment of isolated hepatocytes with p53-inducing agents (DEN, taxol, doxorubicin, araC) and TGFalpha.
  • Evaluation of cellular toxicity.

Main Results:

  • The p53 response was significantly attenuated in EAF hepatocytes compared to non-EAF hepatocytes (11 times less frequent).
  • Isolated EAF hepatocytes did not respond to TGFalpha.
  • DEN, taxol, doxorubicin, and araC induced p53 in non-EAF but not in EAF hepatocytes, despite similar taxol-induced toxicity.

Conclusions:

  • The attenuated p53 response in EAF hepatocytes is an in situ phenomenon.
  • Factors beyond altered xenobiotic metabolism contribute to this response.
  • Adaptive alterations in p53 expression control within EAF hepatocytes are likely involved.

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