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Cyclin D1 in low-dose radiation-induced adaptive resistance

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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 14-3-3ζ in unstressed cells and mutation of 14-3-3ζ Ser-58 to Asp (S58D) significantly impaired 14-3-3ζ binding to cyclin D1. The formation of cyclin D1/14-3-3ζ complex was differently regulated by exposure to low (10-cGy X-ray) versus high (5-Gy γ-ray) doses of radiation. Unlike exposure to 5-Gy that predominantly enhanced cyclin D1 nuclear accumulation, LDIR induced the dissociation of the cyclin D1/14-3-3ζ 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 (Δψm) in LDIR-treated cells. Consistently, blocking cyclin D1/Bax formation by cyclin D1 siRNA reversed Δψm 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.

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Abbreviations

Δψm:

mitochondrial membrane potential

DAPI:

4,6-diamidino-2-phenylindole

EYFP:

enhanced yellow fluorescent protein

HDIR:

high-dose ionizing radiation

IHC:

immunohistochemistry

IR:

ionizing radiation

LDIR:

low-dose ionizing radiation

NP-40:

nonidet P-40

PMSF:

phenylmethylsulfonylfluoride

siRNA:

short interfering RNA

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Acknowledgements

We thank Dr N Colburn (National Cancer Institute, NIH) for providing human keratinocytes HK18 cells, Dr S Liu (Purdue University School of Health Sciences) for invaluable help with animal experiments. This work was supported by NIH NCI grant RO1 101990 and the Department of Energy grant DE-FG02-03ER63634 to JJL.

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Authors and Affiliations

  1. Division of Molecular Radiobiology and Graduate Program of Radiation and Cancer Biology, Purdue University School of Health Sciences, West Lafayette, IN, USA

    K M Ahmed, M Fan, D Nantajit, N Cao & J J Li

  2. Purdue Cancer Center, West Lafayette, IN, USA

    J J Li

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  1. K M Ahmed
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  2. M Fan
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  3. D Nantajit
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  4. N Cao
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Correspondence to J J Li.

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Ahmed, K., Fan, M., Nantajit, D. et al. Cyclin D1 in low-dose radiation-induced adaptive resistance. Oncogene 27, 6738–6748 (2008). https://doi.org/10.1038/onc.2008.265

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