Insulin-like growth factor binding protein-6 (IGFBP-6) interacts with DNA-end binding protein Ku80 to regulate cell fate

Cristiana Iosef, Gregory Vilk, Theofanis Gkourasas, Kyung Jong Lee, Benjamin P C Chen, Ping Fu, Leon A. Bach, Gilles Lajoie, Madhulika B. Gupta, Shawn S C Li, Victor K. Han

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Insulin-like growth factor binding protein-6 (IGFBP-6) is a growth inhibitory protein that regulates the availability of insulin-like growth factors (IGFs). We recently reported that IGFBP-6 exerts intracellular actions via its translocation to the nucleus. We now show that IGFBP-6 co-purifies by tandem-affinity with nuclear proteins involved in DNA stability and repair such as Ku80, Ku70, histone H2B and importin-α. Furthermore, this report shows that IGFBP-6 and Ku80 interact specifically using two active binding sites for Ku80 in IGFBP-6. One of the binding sites [196RKR199], as part of the NLS-sequence in IGFBP-6 also binds importin-α which may selectively compete with Ku80 regulating its trafficking to the nucleus. Moreover, IGFBP-6 co-localized with Ku80 based on a cell cycle pattern. Overexpression of IGFBP-6 increased the nuclear Ku80 in mitotic cells and reduced it post-mitosis. It is known that if highly expressed IGFBP-6 induces apoptosis and in our model, the down-regulation of Ku80 by specific siRNAs enhanced the apoptotic effect caused by the IGFBP-6 overexpression. This study demonstrates that IGFBP-6 alters cell survival by potentially regulating the availability of Ku80 for the DNA-repair process. This action represents a novel mechanism by which growth inhibitory proteins such as IGFBP-6 regulate cell fate.

Original languageEnglish (US)
Pages (from-to)1033-1043
Number of pages11
JournalCellular Signalling
Volume22
Issue number7
DOIs
StatePublished - Jul 1 2010

    Fingerprint

Keywords

  • Apoptosis
  • DNA repair
  • IGFBP-6
  • Ku proteins

ASJC Scopus subject areas

  • Cell Biology

Cite this