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1 June 2006 Increased Radioresistance, G2/M Checkpoint Inhibition, and Impaired Migration of Bone Marrow Stromal Cell Lines Derived from Smad3−/− Mice
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Abstract

Epperly, M. W., Goff, J. P., Zhang, X., Niu, Y., Shields, D. S., Wang, H., Shen, H., Franicola, D., Bahnson, A. B., Nie, S., Greenberger, E. E. and Greenberger, J. S. Increased Radioresistance, G2/M Checkpoint Inhibition, and Impaired Migration of Bone Marrow Stromal Cell Lines Derived from Smad3−/− Mice. Radiat. Res. 165, 671–677 (2006).

Smad3 protein is a prominent member of the Tgfb receptor signaling pathway. Smad3−/− mice display decreased radiation-induced skin fibrosis, suggesting a defect in both Tgfb-mediated fibroblast proliferation and migration. We established bone marrow stromal cell lines from Smad3−/− mice and homozygous littermate / mice. Smad3−/− cells displayed a significant increase in radiation resistance with a D0 = 2.25 ± 0.14 Gy compared to Smad3 / cells with a D0 = 1.75 ± 0.03 (P = 0.023). Radioresistance was abrogated by reinsertion of the human SMAD3 transgene, resulting in a D0 = 1.49 0.10 (P = 0.028) for Smad3−/−(3) cells. More Smad3−/− cells than Smad3 / cells were in the G2/M phase; Smad3−/−(3) cells were similar to Smad3 / cells. Smad3 / cells exhibited increased apoptosis 24 h after 5 Gy (15%) or 8 Gy (43%) compared to less than 1% in Smad3−/− cells exposed to either dose. The movement of Smad3−/− cells, measured in an automated cell tracking system, was slower than that of Smad3 / cells. Smad3−/−(3) cells resembled Smad3 / cells. These studies establish concordance of a defective Tgfb signal transduction pathway, an increased proportion of G2/M cells, and radioresistance. The decreased migratory capacity of Smad3−/− cells in vitro correlates with decreased radiation fibrosis in vivo in mice deficient in Tgfb signaling.

Michael W. Epperly, Julie P. Goff, Xichen Zhang, Yunyun Niu, Donna S. Shields, Hong Wang, Hongmei Shen, Darcy Franicola, Alfred B. Bahnson, Suhua Nie, Emily E. Greenberger, and Joel S. Greenberger "Increased Radioresistance, G2/M Checkpoint Inhibition, and Impaired Migration of Bone Marrow Stromal Cell Lines Derived from Smad3−/− Mice," Radiation Research 165(6), (1 June 2006). https://doi.org/10.1667/RR3572.1
Received: 1 December 2005; Accepted: 1 February 2006; Published: 1 June 2006
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