Cyclin D1 in low-dose radiation-induced adaptive resistance.
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.
Ahmed
K M
KM
Division of Molecular Radiobiology and Graduate Program of Radiation and Cancer Biology, Purdue University School of Health Sciences, West Lafayette, IN 47907, USA.
Fan
M
M
Nantajit
D
D
Cao
N
N
Li
J J
JJ
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000528:radiation effects; D019943:Amino Acid Substitution; D017209:Apoptosis / Q000528:radiation effects*; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000528:radiation effects; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D034741:RNA, Small Interfering / Q000235:genetics; D014965:X-Rays; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D048948:14-3-3 Proteins; C494826:BAX protein, human; C530104:CCND1 protein, human; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D019938:Cyclin D1