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Mcl-1 Depletion in Apoptosis Elicited by Ionizing Radiation in Peritoneal Resident Macrophages of C3H Mice

Yoshihisa Kubota^1,*, Keiji Kinoshita^*, Katsutoshi Suetomi^*, Akira Fujimori^* and Sentaro Takahashi

^* Environmental and Toxicological Sciences Research Group, National Institute of Radiological Sciences, Chiba, Japan; and National Institute of Radiological Sciences, Chiba, Japan

Remarkably, apoptosis was induced by exposing peritoneal resident macrophages (PRM) of C3H mice, but not other strains of mice, to ionizing radiation. The molecular mechanism of this strain-specific apoptosis in PRM was studied. The apoptosis elicited in C3H mouse PRM 4 h after exposure was effectively blocked by proteasome inhibitors. Irradiation-induced disruption of mitochondrial transmembrane potential and the release of cytochrome c into the cytosol were also suppressed by a proteasome inhibitor but not by a caspase inhibitor. To determine whether the apoptosis occurred due to a depletion of antiapoptotic proteins, Bcl-2 family proteins were examined. Irradiation markedly decreased the level of Mcl-1, but not Bcl-2, Bcl-X_L, Bax, A1, or cIAP1. Mcl-1’s depletion was suppressed by a proteasome inhibitor but not by a caspase inhibitor. The amount of Mcl-1 was well correlated with the rate of apoptosis in C3H mouse PRM exposed to irradiation and not affected by irradiation in radioresistant B6 mouse PRM. Irradiation increased rather than decreased the Mcl-1 mRNA expression in C3H mouse PRM. On the other hand, Mcl-1 protein synthesis was markedly suppressed by irradiation. Global protein synthesis was also suppressed by irradiation in C3H mouse PRM but not in B6 mouse PRM. The down-regulation of Mcl-1 expression with Mcl-1-specific small interfering RNA or antisense oligonucleotide significantly induced apoptosis in both C3H and B6 mouse PRM without irradiation. It was concluded that the apoptosis elicited in C3H mouse PRM by ionizing radiation was attributable to the depletion of Mcl-1 through radiation-induced arrest of global protein synthesis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Yoshihisa Kubota, Environmental and Toxicological Sciences Research Group, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. E-mail address: y_kubota{at}nirs.go.jp

² Abbreviations used in this paper: PRM, peritoneal resident macrophage; ATM, ataxia telangiectasia mutated; GusB, glucuronidase ; HVJ, Hemagglutinating Virus of Japan; MEF, mouse embryonic fibroblast; RIPA, radioimmunoprecipitation assay; siRNA, small interfering RNA; TP53, tumor protein 53.

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