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Ultraviolet irradiation blocks cellular responses to transforming growth factor-beta by down-regulating its type-II
1Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, 48109-0609, USA.
Abstract:
Transforming growth factor-beta (TGF-beta) is a multi-functional cytokine that regulates cell growth and differentiation. Cellular responses to TGF-beta 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 TGF-beta-induced Smad2/3-mediated gene expression. UV irradiation inhibited TGF-beta-induced phosphorylation of Smad2 and subsequent nuclear translocation and DNA binding of Smad2/3. Specific cell surface binding of TGF-beta was substantially reduced after UV irradiation. This loss of TGF-beta binding resulted from UV-induced down-regulation of TGF-beta type II receptor (T beta RII) mRNA and protein. UV irradiation significantly inhibited T beta RII promoter reporter constructs, indicating that UV reduction of T beta RII expression involved transcriptional repression. In contrast to its effects on T beta RII, UV 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 induced by UV irradiation inhibited TGF-beta-induced gene expression 30%. Maintaining T beta RII levels by overexpression of T beta RII prevented UV inhibition of TGF-beta responsiveness. Taken together, these data indicate that UV irradiation blocks cellular responsiveness to TGF-beta through two mechanisms that impair TGF-beta receptor function. The primary mechanism is down-regulation of T beta RII, and the secondary mechanism is induction of Smad7.
Insights
UV irradiation inhibits cellular responses to transforming growth factor-beta (TGF-beta) by reducing TGF-beta type II receptor (TβRII) expression and increasing Smad7, a TGF-beta signaling inhibitor.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Transforming growth factor-beta (TGF-beta) is a crucial cytokine regulating cell growth and differentiation.
- Cellular responses to TGF-beta are mediated by a cell surface receptor complex activating Smad2 and Smad3 transcription factors.
Purpose of the Study:
- To investigate the mechanisms by which UV irradiation inhibits TGF-beta-induced gene expression in mink lung epithelial cells.
- To elucidate the roles of TGF-beta type II receptor (TβRII) and Smad7 in UV-induced suppression of TGF-beta signaling.
Main Methods:
- UV irradiation of mink lung epithelial cells.
- Analysis of TGF-beta signaling pathway components, including Smad2/3 phosphorylation, nuclear translocation, and DNA binding.
- Measurement of TβRII and Smad7 mRNA and protein levels.
- Reporter gene assays to assess promoter activity of TβRII and Smad7.
- Overexpression studies of TβRII and Smad7.
Main Results:
- UV irradiation significantly inhibited TGF-beta-induced Smad2/3-mediated gene expression.
- UV exposure reduced TGF-beta binding, TβRII mRNA and protein levels, and TβRII promoter activity.
- UV irradiation rapidly induced Smad7 mRNA and protein, increasing Smad7 promoter activity.
- Overexpression of Smad7 partially inhibited TGF-beta signaling, while TβRII overexpression prevented UV-induced inhibition.
Conclusions:
- UV irradiation impairs cellular responsiveness to TGF-beta primarily through TβRII downregulation.
- A secondary mechanism involves UV-induced Smad7 upregulation, which antagonizes TGF-beta signaling.
- These findings reveal dual mechanisms by which UV radiation disrupts TGF-beta receptor function and downstream signaling.