상피세포에서 DNA 손상 저해를 통한 TGF-beta1의 방사선 손상 보호 효과

Abstract

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates various cellular responses on a variety of cell types. Several groups have suggested that TGF-beta regulates activation of DNA-damage response upon irradiation, which results in either cell survival or apoptosis depending on the cellular context. However, how TGF-beta controls the cell fate upon irradiation has not been fully understood yet. In the present study, we investigated the effects of TGF-beta1 on DNA-damage responses and cell death by irradiation in epithelial cells. Twenty-four hour pretreatment of TGF-beta1 protected cells from apoptosis in response to irradiation based on Annexin V staining and DNA fragmentation. Consistently, reduced activations of Caspase-9 and Caspase-3 and cleavage of PARP were detected in TGF-beta1-pretreated A431 and HaCaT cells. To explore possible mechanisms for the apoptosis, we examined the DNA damage response. Six and twenty-four hour after irradiation, length of comet tail, gamma-H2AX foci formation, and phosphorylation of ATM, Chk2, and p53 were reduced by TGF-beta1 treatment. Type I TGF-beta receptor (TbRI) inhibitor, SB431542, inhibited these radio-protective effect of TGF-beta1 on three dimensional culture and in vivo study. Overall, these data suggest that TGF-beta1 protects cells from gamma-irradiation-induced apoptosis by attenuating DNA damage.