Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores

J Cell Biol. 2003 Apr 28;161(2):267-80. doi: 10.1083/jcb.200208091.

Abstract

The Aurora/Ipl1 family of protein kinases plays multiple roles in mitosis and cytokinesis. Here, we describe ZM447439, a novel selective Aurora kinase inhibitor. Cells treated with ZM447439 progress through interphase, enter mitosis normally, and assemble bipolar spindles. However, chromosome alignment, segregation, and cytokinesis all fail. Despite the presence of maloriented chromosomes, ZM447439-treated cells exit mitosis with normal kinetics, indicating that the spindle checkpoint is compromised. Indeed, ZM447439 prevents mitotic arrest after exposure to paclitaxel. RNA interference experiments suggest that these phenotypes are due to inhibition of Aurora B, not Aurora A or some other kinase. In the absence of Aurora B function, kinetochore localization of the spindle checkpoint components BubR1, Mad2, and Cenp-E is diminished. Furthermore, inhibition of Aurora B kinase activity prevents the rebinding of BubR1 to metaphase kinetochores after a reduction in centromeric tension. Aurora B kinase activity is also required for phosphorylation of BubR1 on entry into mitosis. Finally, we show that BubR1 is not only required for spindle checkpoint function, but is also required for chromosome alignment. Together, these results suggest that by targeting checkpoint proteins to kinetochores, Aurora B couples chromosome alignment with anaphase onset.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase / drug effects
  • Anaphase / genetics*
  • Aurora Kinase B
  • Aurora Kinases
  • Benzamides / pharmacology
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosome Segregation / drug effects
  • Chromosome Segregation / genetics*
  • DNA Replication / drug effects
  • DNA Replication / genetics
  • Enzyme Inhibitors / pharmacology
  • Eukaryotic Cells / drug effects
  • Eukaryotic Cells / enzymology*
  • Eukaryotic Cells / ultrastructure
  • Genes, cdc / drug effects
  • HeLa Cells
  • Humans
  • Kinetochores / drug effects
  • Kinetochores / metabolism*
  • Mad2 Proteins
  • Mitosis / drug effects
  • Mitosis / genetics*
  • Paclitaxel / pharmacology
  • Phosphorylation / drug effects
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics*
  • Quinazolines / pharmacology
  • Repressor Proteins / drug effects
  • Repressor Proteins / genetics
  • Spindle Apparatus / drug effects
  • Spindle Apparatus / genetics
  • Tumor Suppressor Protein p53 / drug effects
  • Tumor Suppressor Protein p53 / genetics

Substances

  • 4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline
  • Benzamides
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Enzyme Inhibitors
  • MAD2L1 protein, human
  • Mad2 Proteins
  • Quinazolines
  • Repressor Proteins
  • Tumor Suppressor Protein p53
  • centromere protein E
  • Protein Kinases
  • AURKB protein, human
  • Aurora Kinase B
  • Aurora Kinases
  • BUB1 protein, human
  • Bub1 spindle checkpoint protein
  • Protein Serine-Threonine Kinases
  • Paclitaxel