Ultraviolet Irradiation Blocks Cellular Responses to Transforming Growth Factor-β by Down-regulating Its Type-II Receptor and Inducing Smad7

Abstract

Transforming growth factor-β (TGF-β) is a multi-functional cytokine that regulates cell growth and differentiation. Cellular responses to TGF-β are mediated through its cell surface receptor complex, which activates transcription factors Smad2 and Smad3. Here we report that UV irradiation of mink lung epithelial cells causes near complete inhibition of TFG-β-induced Smad2/3-mediated gene expression. UV irradiation inhibited TGF-β-induced phosphorylation of Smad2 and subsequent nuclear translocation and DNA binding of Smad2/3. Specific cell surface binding of TGF-β was substantially reduced after UV irradiation. This loss of TGF-β binding resulted from UV-induced down-regulation of TGF-β type II receptor (TβRII) mRNA and protein. UV irradiation significantly inhibited TβRII promoter reporter constructs, indicating that UV reduction of TβRII expression involved transcriptional repression. In contrast to its effects on TβRII, UV irradiation rapidly induced Smad7 mRNA and protein. Smad7 is known to antagonize activation of Smad2/3 and thereby block TGF-β-dependent gene expression. UV irradiation stimulated Smad7 promoter reporter constructs, indicating that increased Smad7 expression resulted, at least in part, from increased transcription. Overexpression of Smad7 protein to the level induced by UV irradiation inhibited TGF-β-induced gene expression 30%. Maintaining TβRII levels by overexpression of TβRII prevented UV inhibition of TGF-β responsiveness. Taken together, these data indicate that UV irradiation blocks cellular responsiveness to TGF-β through two mechanisms that impair TGF-β receptor function. The primary mechanism is down-regulation of TβRII, and the secondary mechanism is induction of Smad7.