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Related Experiment Videos

MAPK mediates RAS-induced chromosome instability.

H I Saavedra1, K Fukasawa, C W Conn

  • 1Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521, USA.

The Journal of Biological Chemistry
|December 23, 1999
PubMed
Summary

The MAPK pathway mediates micronucleus formation, a sign of DNA damage. Inhibiting this pathway reduces micronuclei, while its activation increases them, indicating its role in chromosome instability.

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Area of Science:

  • Cell Biology
  • Genetics
  • Molecular Biology

Background:

  • Micronuclei formation indicates DNA damage, mitotic defects, and genetic material loss.
  • The Mitogen-Activated Protein Kinase (MAPK) pathway is implicated in cellular stress responses.

Purpose of the Study:

  • To investigate the role of the MAPK pathway in mediating v-ras-induced micronucleus formation in NIH 3T3 cells.
  • To determine if constitutive MAPK activation influences chromosome instability.

Main Methods:

  • Inhibition of MAPK activation using specific kinase inhibitors (PD98059, U0126).
  • Constitutive activation of the MAPK pathway via v-mos retrovirus infection.
  • Analysis of micronuclei using CREST antibody staining to identify chromosome loss and segregation errors.

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Main Results:

  • MAPK kinase inhibitors PD98059 and U0126 significantly reduced micronucleus formation.
  • Wortmannin, a Ras/phosphatidylinositol 3-kinase inhibitor, did not affect micronucleus formation.
  • Constitutive MAPK activation by v-mos increased micronucleus formation, predominantly CREST-positive (lost chromosomes) and some CREST-negative (acentric fragments).
  • Observed instability included bi-nucleated cells, centrosome amplification, and mitotic chromosome bridges, indicating mitotic aberrations.

Conclusions:

  • The MAPK pathway plays a crucial role in mediating micronucleus formation and chromosome instability.
  • Constitutive MAPK activation leads to chromosome loss and segregation errors, primarily through aberrant mitosis.
  • Mitotic aberrations, including spindle perturbations and cytokinesis failure, are key mechanisms underlying MAPK-mediated chromosome instability.