Id-1 promotes chromosomal instability through modification of APC/C activity during mitosis in response to microtubule disruption

Oncogene. 2008 Jul 24;27(32):4456-66. doi: 10.1038/onc.2008.87. Epub 2008 Mar 31.

Abstract

Id-1 (Inhibitor of DNA binding/differential-1) plays a positive role in tumorigenesis through regulation of multiple signaling pathways. Recently, it is suggested that upregulation of Id-1 in cancer cells promotes chromosomal instability. However, the underlying molecular mechanism is not known. In this study, we report a novel function of Id-1 in regulation of mitosis through physical interaction with Cdc20 (cell division cycle protein 20) and Cdh1 (Cdc20 homolog 1). During early mitosis, Id-1 interacts with Cdc20 and RASSF1A (Ras association domain family 1A), leading to enhanced APC(Cdc20) activity, which in turn promotes cyclin B1/securin degradation and premature mitosis. During late mitosis, Id-1 binds to Cdh1 and disrupts the interaction between Cdh1 and APC, resulting in suppression of APC(Cdh1) activity. On the other hand, overexpression of Cdh1 leads to Id-1 protein degradation, suggesting that Id-1 may also act as a substrate of APC(Cdh1). The negative effect of Id-1 on APC(Cdh1) results in suppression of APC(Cdh1)-induced Aurora A and Cdc20 degradation, leading to failure in cytokinesis. As a result, overexpression of Id-1 in human prostate epithelial cells leads to polyploidy in response to microtubule disruption, and this effect is abolished when Id-1 expression is suppressed using antisense technology. These results demonstrate a novel function of Id-1 in promoting chromosomal instability through modification of APC/C activity during mitosis and provide a novel molecular mechanism accounted for the function of Id-1 as an oncogene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome
  • Aurora Kinases
  • Cdc20 Proteins
  • Cell Cycle Proteins / physiology*
  • Cell Line
  • Chromosomal Instability*
  • Cyclin B / metabolism
  • Cyclin B1
  • G1 Phase
  • Humans
  • Inhibitor of Differentiation Protein 1 / physiology*
  • Microtubules / physiology*
  • Mitosis*
  • Protein Serine-Threonine Kinases / metabolism
  • Tumor Suppressor Proteins / physiology
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligase Complexes / physiology*

Substances

  • CCNB1 protein, human
  • Cdc20 Proteins
  • Cell Cycle Proteins
  • Cyclin B
  • Cyclin B1
  • Inhibitor of Differentiation Protein 1
  • RASSF1 protein, human
  • Tumor Suppressor Proteins
  • Ubiquitin
  • CDC20 protein, human
  • Ubiquitin-Protein Ligase Complexes
  • Anaphase-Promoting Complex-Cyclosome
  • Aurora Kinases
  • Protein Serine-Threonine Kinases