Cyclin D1 in low-dose radiation-induced adaptive resistance

Oncogene. 2008 Dec 4;27(53):6738-48. doi: 10.1038/onc.2008.265. Epub 2008 Aug 11.

Abstract

Cyclin D1 is involved in cell-cycle arrest in DNA-damage response. This study tested the hypothesis that cyclin D1 regulates mitochondrial apoptosis. Cyclin D1 was induced by low-dose ionizing radiation (LDIR; 10-cGy X-ray) in human keratinocytes with an adaptive radioresistance that can be inhibited by short interfering RNA (siRNA)-mediated cyclin D1 inhibition. Cyclin D1 was found to form complex with chaperon 14-3-3zeta in unstressed cells and mutation of 14-3-3zeta Ser-58 to Asp (S58D) significantly impaired 14-3-3zeta binding to cyclin D1. The formation of cyclin D1/14-3-3zeta complex was differently regulated by exposure to low (10-cGy X-ray) versus high (5-Gy gamma-ray) doses of radiation. Unlike exposure to 5-Gy that predominantly enhanced cyclin D1 nuclear accumulation, LDIR induced the dissociation of the cyclin D1/14-3-3zeta complex without nuclear translocation, indicating that cytosolic accumulation of cyclin D1 was required for LDIR-induced adaptive response. Further studies revealed a direct interaction of cyclin D1 with proapoptotic Bax and an improved mitochondrial membrane potential (Deltapsi(m)) in LDIR-treated cells. Consistently, blocking cyclin D1/Bax formation by cyclin D1 siRNA reversed Deltapsi(m) and inhibited the LDIR-associated antiapoptotic response. These results demonstrate the evidence that cytosolic cyclin D1 is able to regulate apoptosis by interaction with Bax in LDIR-induced adaptive resistance.

Publication types

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

MeSH terms

  • 14-3-3 Proteins / genetics
  • 14-3-3 Proteins / metabolism
  • Active Transport, Cell Nucleus / radiation effects
  • Amino Acid Substitution
  • Apoptosis / radiation effects*
  • Cell Line
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism*
  • Dose-Response Relationship, Radiation
  • Gamma Rays*
  • Humans
  • Membrane Potential, Mitochondrial / radiation effects
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Mutation, Missense
  • RNA, Small Interfering / genetics
  • X-Rays*
  • bcl-2-Associated X Protein / antagonists & inhibitors
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism

Substances

  • 14-3-3 Proteins
  • BAX protein, human
  • CCND1 protein, human
  • Molecular Chaperones
  • Multiprotein Complexes
  • RNA, Small Interfering
  • bcl-2-Associated X Protein
  • Cyclin D1