Centriole overduplication through the concurrent formation of multiple daughter centrioles at single maternal templates

Oncogene. 2007 Sep 20;26(43):6280-8. doi: 10.1038/sj.onc.1210456. Epub 2007 Apr 16.

Abstract

Abnormal centrosome numbers are detected in virtually all cancers. The molecular mechanisms that underlie centrosome amplification, however, are poorly characterized. Based on the model that each maternal centriole serves as a template for the formation of one and only one daughter centriole per cell division cycle, the prevailing view is that centriole overduplication arises from successive rounds of centriole reproduction. Here, we provide evidence that a single maternal centriole can concurrently generate multiple daughter centrioles. This mechanism was initially identified in cells treated with the peptide vinyl sulfone proteasome inhibitor Z-L(3)VS. We subsequently found that the formation of more than one daughter at maternal centrioles requires cyclin E/cyclin-dependent kinase 2 as well as Polo-like kinase 4 and that overexpression of these proteins mimics this phenotype in the absence of a proteasome inhibitor. Moreover, we show that the human papillomavirus type 16 E7 oncoprotein stimulates aberrant daughter centriole numbers in part through the formation of more than one daughter centriole at single maternal templates. These results help to explain how oncogenic stimuli can rapidly induce abnormal centriole numbers within a single cell-division cycle and provide insights into the regulation of centriole duplication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Centrioles / drug effects
  • Centrioles / metabolism*
  • Centrioles / ultrastructure
  • Cyclin E / genetics
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2 / genetics
  • Cyclin-Dependent Kinase 2 / metabolism
  • Humans
  • Microscopy, Electron
  • Mitosis
  • Oligopeptides / pharmacology
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism
  • Papillomavirus E7 Proteins
  • Protease Inhibitors / pharmacology
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Spindle Apparatus / metabolism
  • Sulfones / pharmacology

Substances

  • Cyclin E
  • Oligopeptides
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Sulfones
  • carboxybenzyl-leucyl-leucyl-leucine vinyl sulfone
  • oncogene protein E7, Human papillomavirus type 16
  • PLK4 protein, human
  • Protein-Serine-Threonine Kinases
  • Cyclin-Dependent Kinase 2
  • Proteasome Endopeptidase Complex