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
References
Ahmed KM, Dong S, Fan M, Li JJ . (2006). Nuclear factor κB P65 inhibits mitogen-activated protein kinase signaling pathway in radioresistant breast cancer cells. Mol Cancer Res 4: 945–955.
Biliran Jr H, Wang Y, Banerjee S, Xu H, Heng H, Thakur A et al. (2005). Overexpression of cyclin D1 promotes tumor cell growth and confers resistance to cisplatin-mediated apoptosis in an elastase-myc transgene-expressing pancreatic tumor cell line. Clin Cancer Res 11: 6075–6086.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96: 857–868.
Chen X, Shen B, Xia L, Khaletzkiy A, Chu D, Wong JY et al. (2002). Activation of nuclear factor kappaB in radioresistance of TP53-inactive human keratinocytes. Cancer Res 62: 1213–1221.
Costantini P, Jacotot E, Decaudin D, Kroemer G . (2000). Mitochondrion as a novel target of anticancer chemotherapy. J Natl Cancer Inst 92: 1042–1053.
Daosukho C, Kiningham K, Kasarskis EJ, Ittarat W, St Clair DK . (2002). Tamoxifen enhancement of TNF-alpha induced MnSOD expression: modulation of NF-kappaB dimerization. Oncogene 21: 3603–3610.
Fan M, Ahmed KM, Coleman MC, Spitz DR, Li JJ . (2007). Nuclear factor-kappaB and manganese superoxide dismutase mediate adaptive radioresistance in low-dose irradiated mouse skin epithelial cells. Cancer Res 67: 3220–3228.
Feinendegen LE, Bond VP, Sondhaus CA, Muehlensiepen H . (1996). Radiation effects induced by low doses in complex tissue and their relation to cellular adaptive responses. Mutat Res 358: 199–205.
Guo G, Yan-Sanders Y, Lyn-Cook BD, Wang T, Tamae D, Ogi J et al. (2003). Manganese superoxide dismutase-mediated gene expression in radiation-induced adaptive responses. Mol Cell Biol 23: 2362–2378.
Hermeking H, Lengauer C, Polyak K, He TC, Zhang L, Thiagalingam S et al. (1997). 14-3-3 Sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell 1: 3–11.
Hu CD, Chinenov Y, Kerppola TK . (2002). Visualization of interactions among bZIP and Rel family proteins in living cells using bimolecular fluorescence complementation. Mol Cell 9: 789–798.
Karbowski M, Norris KL, Cleland MM, Jeong SY, Youle RJ . (2006). Role of Bax and Bak in mitochondrial morphogenesis. Nature 443: 658–662.
Kelsey KT, Memisoglu A, Frenkel D, Liber HL . (1991). Human lymphocytes exposed to low doses of X-rays are less susceptible to radiation-induced mutagenesis. Mutat Res 263: 197–201.
Klokov D, Criswell T, Leskov KS, Araki S, Mayo L, Boothman DA . (2004). IR-inducible clusterin gene expression: a protein with potential roles in ionizing radiation-induced adaptive responses, genomic instability, and bystander effects. Mutat Res 568: 97–110.
Limoli CL, Kaplan MI, Giedzinski E, Morgan WF . (2001). Attenuation of radiation-induced genomic instability by free radical scavengers and cellular proliferation. Free Radic Biol Med 31: 10–19.
Nomura M, Shimizu S, Sugiyama T, Narita M, Ito T, Matsuda H et al. (2003). 14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax. J Biol Chem 278: 2058–2065.
Oyama T, Kashiwabara K, Yoshimoto K, Arnold A, Koerner F . (1998). Frequent overexpression of the cyclin D1 oncogene in invasive lobular carcinoma of the breast. Cancer Res 58: 2876–2880.
Pandey BN, Gordon DM, De Toledo SM, Pain D, Azzam EI . (2006). Normal human fibroblasts exposed to high- or low-dose ionizing radiation: differential effects on mitochondrial protein import and membrane potential. Antioxid Redox Signal 8: 1253–1261.
Paulovich AG, Toczyski DP, Hartwell LH . (1997). When checkpoints fail. Cell 88: 315–321.
Powell DW, Rane MJ, Joughin BA, Kalmukova R, Hong JH, Tidor B et al. (2003). Proteomic identification of 14-3-3zeta as a mitogen-activated protein kinase-activated protein kinase 2 substrate: role in dimer formation and ligand binding. Mol Cell Biol 23: 5376–5387.
Qi W, Martinez JD . (2003). Reduction of 14-3-3 proteins correlates with increased sensitivity to killing of human lung cancer cells by ionizing radiation. Radiat Res 160: 217–223.
Rothkamm K, Lobrich M . (2003). Evidence for a lack of DNA double-strand break repair in human cells exposed to very low X-ray doses. Proc Natl Acad Sci USA 100: 5057–5062.
Sakamaki T, Casimiro MC, Ju X, Quong AA, Katiyar S, Liu M et al. (2006). Cyclin D1 determines mitochondrial function in vivo. Mol Cell Biol 26: 5449–5469.
Shadley JD, Afzal V, Wolff S . (1987). Characterization of the adaptive response to ionizing radiation induced by low doses of X rays to human lymphocytes. Radiat Res 111: 511–517.
Sherr CJ . (1994). G1 phase progression: cycling on cue. Cell 79: 551–555.
Sumrejkanchanakij P, Tamamori-Adachi M, Matsunaga Y, Eto K, Ikeda MA . (2003). Role of cyclin D1 cytoplasmic sequestration in the survival of postmitotic neurons. Oncogene 22: 8723–8730.
Ulsh BA, Miller SM, Mallory FF, Mitchel RE, Morrison DP, Boreham DR . (2004). Cytogenetic dose–response and adaptive response in cells of ungulate species exposed to ionizing radiation. J Environ Radioact 74: 73–81.
Wang T, Hu YC, Dong S, Fan M, Tamae D, Ozeki M et al. (2005). Co-activation of ERK, NF-kappaB, and GADD45beta in response to ionizing radiation. J Biol Chem 280: 12593–12601.
Xiao B, Smerdon SJ, Jones DH, Dodson GG, Soneji Y, Aitken A et al. (1995). Structure of a 14-3-3 protein and implications for coordination of multiple signalling pathways. Nature 376: 188–191.
Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J et al. (1997). Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275: 1129–1132.
Yoshida K, Yamaguchi T, Natsume T, Kufe D, Miki Y . (2005). JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage. Nat Cell Biol 7: 278–285.
Zhang L, Yu J, Park BH, Kinzler KW, Vogelstein B . (2000). Role of BAX in the apoptotic response to anticancer agents. Science 290: 989–992.
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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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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DOI: https://doi.org/10.1038/onc.2008.265
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