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

Published on: August 4, 2019

Thyroid hormone promotes serine phosphorylation of p53 by mitogen-activated protein kinase

A Shih1, H Y Lin, F B Davis

  • 1Stratton VA Medical Center, Molecular and Cellular Medicine Program, Department of Medicine, Albany Medical College, and Wadsworth Center, New York State Department of Health, Albany, New York 12208, USA.

Biochemistry
|March 22, 2001
PubMed

Insights

Thyroid hormone L-Thyroxine (T4) non-genomically promotes the interaction between mitogen-activated protein kinase (MAPK) and p53. This T4-directed MAPK-p53 interaction alters p53 transcriptional activity.

Area of Science:

  • Molecular Endocrinology
  • Cell Signaling
  • Cancer Biology

Background:

  • L-Thyroxine (T4) exerts nongenomic effects, including promoting nuclear interactions between MAPK and thyroid hormone receptor TRbeta1 (TR), leading to TR serine phosphorylation.
  • The tumor suppressor protein p53 interacts with TRbeta1 and is phosphorylated by various kinases.

Purpose of the Study:

  • To investigate if T4 modulates the association between p53 and TR.
  • To determine if MAPK-mediated serine phosphorylation of p53 is involved in this T4 effect.

Main Methods:

  • Utilized 293T human kidney cells treated with physiological T4 concentrations.
  • Employed nuclear fractionation, immunoprecipitation, and immunoblotting to analyze protein complex formation.
  • Investigated the role of MAPK kinase (MEK) inhibitors (PD 98059, U0126) and MEK antisense oligonucleotides.

Main Results:

  • T4 treatment time-dependently increased p53 accumulation in activated MAPK immunoprecipitates from cell nuclei.
  • T4-induced nuclear complexing of p53 and MAPK was inhibited by MEK inhibitors and absent in MEK-deficient cells.
  • T4 also promoted nuclear co-immunoprecipitation of TRbeta1 and p53, an effect blocked by PD 98059.
  • MAPK directly phosphorylated p53 in vitro, confirming p53 as a MAPK substrate.
  • T4 inhibited p53 transcriptional activity, indicated by reduced c-Jun accumulation, an effect reversed by MEK inhibition.

Conclusions:

  • T4 non-genomically induces the formation of a nuclear complex involving MAPK and p53.
  • MAPK directly phosphorylates p53, modulating its transcriptional activity.
  • This T4-directed MAPK-p53 interaction influences p53's role in gene regulation.

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