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Molecular Factors Affecting Cell Division01:27

Molecular Factors Affecting Cell Division

Several external and internal factors influence the initiation and inhibition of cell division. For instance, the death of nearby cells or the release of human growth hormone (hGH) promotes cell division. In contrast, lack of hGH or crowding of cells can inhibit cell division.
Several proteins function as internal regulators to ensure each cell cycle stage is completed faithfully before proceeding to the next. Regulator molecules may act directly or influence the activity or production of other...

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Probing cell-division phenotype space and Polo-like kinase function using small molecules.

Ulf Peters1, Joseph Cherian, Jeffrey H Kim

  • 1Laboratory of Chemistry and Cell Biology, Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.

Nature Chemical Biology
|October 10, 2006
PubMed
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A small library of diaminopyrimidines (DAPs) identified novel cell-division inhibitors. One inhibitor targeting Polo-like kinases (Plks) disrupts mitotic spindle assembly, offering new tools for cell biology research.

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Area of Science:

  • Cell Biology
  • Chemical Biology
  • Molecular Pharmacology

Background:

  • Cell-permeable small molecules are crucial for probing cell division mechanisms.
  • Phenotype-based screens with chemical libraries identify such inhibitors.
  • The optimal characteristics of compound libraries for exploring cell division phenotypes remain unknown.

Purpose of the Study:

  • To investigate the cell-division phenotype space covered by a small chemical library.
  • To identify novel chemical probes targeting distinct cell division mechanisms.
  • To explore the role of Polo-like kinases (Plks) in mitotic spindle regulation.

Main Methods:

  • Utilized a library of 100 diaminopyrimidines (DAPs) for phenotype-based screening.
  • Employed high-resolution live-cell microscopy to observe cell division dynamics.
  • Applied chemical inhibitors to investigate the function of specific kinases.

Main Results:

  • A small DAP collection induced diverse cell division phenotypes, including altered spindle geometry and mitotic index.
  • Four inhibitors, including a Polo-like kinase (Plk) inhibitor, induced monopolar mitotic spindles.
  • Plk activity was found essential for bipolar mitotic spindle assembly and maintenance.
  • Plk inhibition led to destabilization of kinetochore microtubules, resulting in monopolar spindles.

Conclusions:

  • Small collections of compounds based on privileged scaffolds, like DAPs, can effectively probe cell division phenotype space.
  • The identified Plk inhibitor provides a valuable tool for studying mitotic spindle regulation.
  • These findings suggest potential for developing new cell division probes and antimitotic agents.