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Real-Time Monitoring of Aurora kinase A Activation using Conformational FRET Biosensors in Live Cells
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Real-Time Monitoring of Aurora kinase A Activation using Conformational FRET Biosensors in Live Cells

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Therapeutic potential of mitotic interaction between the nucleoporin Tpr and aurora kinase A

Akiko Kobayashi1, Chieko Hashizume, Takayuki Dowaki

  • 1a Laboratory of Molecular and Cellular Biology; Department of Biology ; Faculty of Natural Systems; Kanazawa University ; Kanazawa , Ishikawa , Japan.

Cell Cycle (Georgetown, Tex.)
|March 20, 2015
PubMed

Insights

Translocated promoter region (Tpr) depletion causes mitotic catastrophe and polyploidy by disrupting Aurora A kinase regulation at centrosomes. Tpr safeguards bipolarity by sequestering excess Aurora A, suggesting therapeutic potential.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Centrosome organization is crucial for spindle bipolarity and genetic integrity.
  • Translocated promoter region (Tpr), a nuclear pore complex component, regulates mitosis and associates with p53.
  • Tpr's role in centrosome function and its interaction with mitotic kinases are not fully understood.

Purpose of the Study:

  • To investigate the role of Tpr in centrosome organization and spindle pole assembly.
  • To elucidate the mechanism by which Tpr influences Aurora A kinase activity and localization.
  • To explore the therapeutic potential of Tpr-Aurora A interactions in cancer.

Main Methods:

  • Depletion of Tpr using RNA interference.
  • Analysis of centrosome structure, spindle organization, and cell cycle progression.
  • Immunofluorescence microscopy to assess protein localization.
  • Western blotting to evaluate protein expression and phosphorylation.
  • Inhibition of Aurora A kinase using Alisertib (MLN8237).

Main Results:

  • Tpr depletion led to mitotic catastrophe, tetraploidy, and polyploidy.
  • Tpr interacts with Aurora A kinase, and its depletion reduces Aurora A expression, localization, and phosphorylation at centrosomes.
  • Inhibition of Aurora A disrupted Tpr localization and induced cell death.
  • Overexpression of Aurora A affected Tpr localization in cells with supernumerary centrosomes.

Conclusions:

  • Tpr plays a critical role in spindle pole organization and bipolar spindle assembly, extending beyond its canonical nuclear pore functions.
  • Mutual regulation exists between Tpr and Aurora A kinase, essential for maintaining genomic stability.
  • The Tpr central coiled-coil domain's ability to bind and sequester Aurora A highlights its potential as a therapeutic target in cancer treatment.
Keywords:
AURKAalisertibcentriolecentrosometpr

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