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p53 is associated with cellular microtubules and is transported to the nucleus by dynein

P Giannakakou1, D L Sackett, Y Ward

  • 1Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, USA.

Nature Cell Biology
|October 12, 2000
PubMed

Insights

The tumor suppressor protein p53 interacts with microtubules and is transported to the nucleus in a dynein-dependent manner, crucial for its function after DNA damage.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The tumor suppressor protein p53 plays a critical role in cellular responses to DNA damage.
  • Microtubules are essential components of the cytoskeleton involved in intracellular transport.
  • The precise mechanisms regulating p53 nuclear accumulation following DNA damage are not fully understood.

Purpose of the Study:

  • To investigate the association of p53 protein with microtubules.
  • To determine the role of microtubules and motor proteins in p53 nuclear transport.
  • To identify the region of p53 responsible for microtubule binding.

Main Methods:

  • In vivo and in vitro co-immunoprecipitation assays to assess p53-tubulin interaction.
  • Microtubule-disrupting agents (vincristine, paclitaxel) and dynein pathway inhibitors (dynamitin overexpression, anti-dynein antibody) were used.
  • Analysis of p53, mdm2, and p21 protein levels and localization via Western blotting and immunofluorescence.

Main Results:

  • p53 protein physically associates with tubulin and localizes to cellular microtubules.
  • Disruption of microtubules or inhibition of dynein function abrogated nuclear accumulation of p53.
  • The N-terminal 25 amino acids of p53 are essential for its binding to microtubules.
  • Reduced nuclear p53 correlated with decreased expression of downstream targets mdm2 and p21.

Conclusions:

  • Microtubules and the dynein motor protein are crucial for the nuclear transport of p53.
  • Dynein-mediated transport along microtubules facilitates p53 accumulation in the nucleus after DNA damage.
  • The N-terminal region of p53 mediates its interaction with the microtubule transport machinery.

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