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Irradiated homozygous TGF-beta1 knockout fibroblasts show enhanced clonogenic survival as compared with TGF-beta1 wild-type fibroblasts



Irradiated homozygous TGF-beta1 knockout fibroblasts show enhanced clonogenic survival as compared with TGF-beta1 wild-type fibroblasts



International Journal of Radiation Biology 78(5): 331-339



Purpose: To study the role of transforming growth factor beta1 (TGF-beta1) on cellular radiation sensitivity by analysing mouse lung fibroblasts of different TGF-beta1 genotypes. Materials and methods: Heterozygous TGF-beta1 knock-out mice were mated to produce offspring of different TGF-beta1 genotypes as confirmed by PCR-genotyping. Primary lung fibroblast populations were established from new-born animals of specific genotypes (TGF-beta1+/+, TGF-beta1+/-, TGF-beta1-/-). Production of TGF-beta1 was tested by ELISA. TGF-beta1 receptor-II mRNA expression was analysed by RT-PCR. Colony formation of untreated, TGF-beta1-treated and/or irradiated primary lung fibroblasts was determined under different medium conditions. Results: Plating efficiencies under different medium conditions were independent of TGF-beta1 genotype. Production of TGF-beta1 correlated with the genotype: heterozygous TGF-beta1 knock-out fibroblasts (TGF-beta1+/-) produced 60-65% of wild-type (TGF-beta1+/+ cells). As expected, homozygous TGF-beta1 knock-out fibroblasts (TGF-beta1-/-) did not produce TGF-beta1. Radiation exposure significantly enhanced TGF-beta1 production in TGF-beta1+/+ cells by a factor of 2. No such stimulation was observed in TGF-beta1+/- cells. TGF-beta1+/- and especially TGF-beta1-/- cells were significantly more radioresistant than TGF-beta1+/+ cells. TGF-beta1 treatment significantly reduced clonogenic survival for both TGF-beta1+/+ and TGF-beta1-/- cells. TGF-beta1 treatment of TGF-beta1-/- cells resulted in an enhancement of radiation sensitivity. Conclusion: The data are the first direct evidence that TGF-beta1 is a major autocrine regulator of intrinsic radiation sensitivity of mouse lung fibroblasts.

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Accession: 010885594

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PMID: 12020424

DOI: 10.1080/095530002753676200



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