Mitotic kinases: the key to duplication, segregation, and cytokinesis errors, chromosomal instability, and oncogenesis

Pharmacol Ther. 2006 Sep;111(3):974-84. doi: 10.1016/j.pharmthera.2006.02.006. Epub 2006 Apr 17.

Abstract

Chromosomal instability (CIN) and aneuploidy are commonly observed in the vast majority of human solid tumors and in many hematological malignancies. These features are considered defining characteristics of human breast, bladder and kidney cancers since they markedly exceed a 50% aneuploidy frequency. The detection of persistent mitotic kinase over-expression, particularly the Aurora family, and centrosome amplification in precursor/pre-malignant stages, strongly implicate these molecular changes in precipitating the aneuploidy seen in many human neoplasms. Mitotic spindle checkpoint defects may also lead to aneuploid tumors. However, the sustained over-expression and activity of various members of the mitotic kinase families, including Aurora (Aur) (A, B, C), Polo-like (Plk1-4), and Nek (NIMA1-11) in diverse human tumors strongly indicate that these entities are intimately involved in the development of errors in centrosome duplication, chromosome segregation, and cytokinesis. Mitotic kinases have also been implicated in regulating the centrosome cycle, spindle checkpoint and microtubule-kinetochore attachment, spindle assembly, and chromosome condensation. These mitotic kinases are modulated by de-novo synthesis, stability factors, phosphorylation, and ubiquitin-dependent proteolysis. They, in turn, phosphorylate a myriad of centrosomal/mitotic protein substrates, and have the ability to behave as oncogenes (i.e. Aur-A, Plk-1), providing a compelling link between errors in mitosis and oncogenic processes. The recent development of selective small molecule inhibitors of Aurora kinases, in particular, will provide useful tools to ascertain more precisely their role in cancer development. Potent inhibitors of mitotic kinases, when fully developed, have the promise to be effective agents against tumor growth, and possibly, tumor prevention as well.

Publication types

  • Review

MeSH terms

  • Aneuploidy
  • Animals
  • Aurora Kinases
  • Cell Cycle Proteins / physiology
  • Centrosome / physiology
  • Chromosomal Instability*
  • Chromosome Segregation*
  • Cytokinesis*
  • Humans
  • Mitosis*
  • NIMA-Related Kinases
  • Neoplasms / etiology*
  • Neoplasms / genetics
  • Protein Kinases / physiology*
  • Protein-Serine-Threonine Kinases / physiology
  • Proto-Oncogene Proteins / physiology
  • Spindle Apparatus / physiology

Substances

  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • Protein Kinases
  • Aurora Kinases
  • NEK2 protein, human
  • NIMA-Related Kinases
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1