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Protein farnesylation inhibitors cause donut-shaped cell nuclei attributable to a centrosome separation defect

Valerie L R M Verstraeten1, Lana A Peckham, Michelle Olive

  • 1Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA.

Proceedings of the National Academy of Sciences of the United States of America
|March 9, 2011
PubMed

Insights

Protein farnesyltransferase inhibitors (FTIs) disrupt centrosome separation, causing abnormal cell division and donut-shaped nuclei. This research reveals FTIs

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Protein farnesyltransferase inhibitors (FTIs) are used in cancer therapy, but their precise mechanisms remain unclear.
  • FTIs are being investigated for Hutchinson-Gilford progeria syndrome, necessitating a deeper understanding of their effects.
  • Investigating FTI molecular pathways is crucial for optimizing therapeutic applications and understanding side effects.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying the effects of FTIs.
  • To investigate the impact of FTI treatment on cell division and nuclear morphology.
  • To identify key proteins and pathways involved in FTI-induced cellular changes.

Main Methods:

  • Treatment of various cell lines and mouse tissues with FTIs.
  • Microscopic analysis of nuclear shape, centrosome separation, and mitotic progression.
  • Investigation of protein interactions and degradation pathways, including lamin B1 and pericentrin.
  • Genetic manipulation of pericentrin expression and proteasomal degradation pathways.

Main Results:

  • FTI treatment induced centrosome separation defects, leading to donut-shaped nuclei.
  • Donut-shaped nuclei were associated with defects in karyokinesis, aneuploidy, and binucleation.
  • Lamin B1 and proteasome-mediated degradation of pericentrin were identified as critical components in FTI-induced donut formation.
  • Altering pericentrin levels or lamin B1 farnesylation, and modulating proteasomal degradation affected donut formation and binucleation.

Conclusions:

  • FTIs play a significant role in centrosome separation and nuclear morphology.
  • Pericentrin is identified as an indirect target of FTIs, influencing centrosome positioning and spindle formation.
  • These findings provide insights into the anticancer effects of FTIs and their potential in treating progeria.

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