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Expression of CONNEXIN43 Is Highly Sensitive to Ionizing Radiation and Other Environmental Stresses¹

Laboratory of Radiobiology, Harvard School of Public Health, Boston, Massachusetts 02115 [E. I. A., S. M. d. T., J. B. L.], and Department of Radiology, New Jersey Medical School, Newark, New Jersey 07103 [E. I. A., S. M. d. T.]

To gain a greater understanding of the mechanisms underlying the cellular responses to low-dose ionizing radiation, gene expression profiles were examined by microarray analysis of cDNA from confluent human diploid fibroblast cultures exposed to very low fluences of -particles. The data, supported by Northern and Western analyses, indicate that radiation induces a significant up-regulation of CONNEXIN43 expression. This phenomenon was observed in a variety of irradiated cell types. These findings are consistent with our previous observations that connexin43 (cx43)-mediated gap-junction intercellular communication is involved in the bystander response observed in cell cultures exposed to fluences of -particles by which only a very small fraction of the cell nuclei is traversed by a particle track (E. I. Azzam et al., Proc. Natl. Acad. Sci. USA, 98: 473–478, 2001). Increased mRNA levels in cells from irradiated cultures correlated with increased cx43 protein levels by 4 h after irradiation. The induction of cx43 was observed by mean -particle doses as low as 0.16 cGy, and also in cells exposed to -rays, t-butyl hydroperoxide, and hyperthermia. Exposure to these stresses also resulted in post-translational modification of cx43; increased phosphorylation and hyperphosphorylation of the protein was observed. Up-regulation of cx43 expression in ionizing radiation exposed cells correlated with functional communication through gap junctions, as evidenced by dye transfer from irradiated to nonirradiated cells. In contrast, the response after UV radiation varied and was cell type-dependent. Overall, these data suggest a critical role for genes involved in intercellular communication in mediating the cellular responses to a variety of stresses.

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