Ultraviolet irradiation blocks cellular responses to transforming growth factor-beta by down-regulating its Type-II receptor and inducing Smad7

Transforming growth factor-beta (TGF-beta) is a multi-functional cytokine t hat regulates cell growth and differentiation. Cellular responses to TGF-be ta are mediated through its cell surface receptor complex, which activates transcription factors Smad2 and Smad3. Here we report that UV irradiation o f mink lung epithelial cells causes near complete inhibition of TFG-beta -i nduced Smad2/3-mediated gene expression. UV irradiation inhibited TGF-P-ind uced phosphorylation of Smad2 and subsequent nuclear translocation and DNA binding of Smad2/3. Specific cell surface binding of TGF-beta was substanti ally reduced after UV irradiation. This loss of TGF-beta binding resulted f rom W-induced down-regulation of TGF-beta type II receptor (T beta RII) mRN A and protein. UV irradiation significantly inhibited T beta RII promoter r eporter constructs, indicating that UV reduction of T beta RII expression i nvolved transcriptional repression. In contrast to its effects on T beta RI I, W irradiation rapidly induced Smad7 mRNA and protein. Smad7 is known to antagonize activation of Smad2/3 and thereby block TGF-beta -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 indu ced by W irradiation inhibited TGF-beta -induced gene expression 30%, Maint aining T beta RII levels by overexpression of T beta RII prevented UV inhib ition of TGF-beta responsiveness. Taken together, these data indicate that UV irradiation blocks cellular responsiveness to TGF-beta through two mecha nisms that impair TGF-beta receptor function. The primary mechanism is down -regulation of T beta RII, and the secondary mechanism is induction of Smad 7.