A Role for PML3 in Centrosome Duplication and Genome Stability

Mol Cell. 2005 Mar 4;17(5):721-32. doi: 10.1016/j.molcel.2005.02.014.

Abstract

The promyelocytic leukemia gene (PML), which is disrupted by the chromosomal translocation t(15;17) in acute promyelocytic leukemia (APL), encodes a multifunctional protein involved in several important cellular functions. Herein, we demonstrate that PML is localized to centrosomes and that PML deficiency leads to centrosome amplification. By using PML isoform-specific antibodies, we found PML3-specific association with the centrosome and the pole of the mitotic spindle. PML3 deficiency leads to dysregulation of the centrosome duplication checkpoint. Furthermore, PML3 physically interacts with Aurora A and regulates its kinase activity. Specific knockdown of PML3 activates Cdk2/cyclin kinase activity. The results of this study implicate a direct role for PML3 in the control of centrosome duplication through suppression of Aurora A activation to prevent centrosome reduplication.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aurora Kinases
  • Bone Marrow / metabolism
  • CDC2-CDC28 Kinases / metabolism
  • Cell Cycle Proteins
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Centrosome / metabolism
  • Centrosome / ultrastructure
  • Cyclin-Dependent Kinase 2
  • Cytoplasm / metabolism
  • Genome*
  • Humans
  • Immunoprecipitation
  • Mitosis
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Plasmids / metabolism
  • Promyelocytic Leukemia Protein
  • Protein Isoforms
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases
  • RNA, Small Interfering / metabolism
  • Spindle Apparatus
  • Subcellular Fractions / metabolism
  • Time Factors
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Tumor Suppressor Proteins
  • U937 Cells
  • Xenopus Proteins

Substances

  • Cell Cycle Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • Promyelocytic Leukemia Protein
  • Protein Isoforms
  • RNA, Small Interfering
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Xenopus Proteins
  • PML protein, human
  • Protein Kinases
  • AURKA protein, Xenopus
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2