Signaling Pathway by which TGF-β1 Increases Expression of Latent TGF-β Binding Protein-2 at the Transcriptional Level

Abstract

The cytokine transforming growth factor-β has multiple effects on a wide variety of cell types. These effects include modulation of growth and regulation of gene transcription. In the present work, we demonstrate that TGF-βl increases transcription of the latent transforming growth factor+ binding protein-2 (LTBP-2) gene in cultured human fetal lung fibroblasts leading to a significant increase in LTBP-2 mRNA steady state level. The stability of LTBP-2 mRNA was not appreciably altered. A corresponding increase in production of LTBP-2 protein accompanied the increase in mRNA. Through the use of specific inhibitors, we demonstrate that a member of the Ras super family and a protein kinase C, probably of the atypical (non-diacylglycerol, non-Ca⁺⁺ dependent) class are likely to he components in the signaling pathway. However, phospholipases, C proteins and extracellular-signal regulated kinases do not appear to be involved. These results combined with previous findings on elastin regulation by TGF-β1 (Kucich et al. (1997). Am. J. Respir. Cell Mol. Biol., 17: 10-16) demonstrate that TGF-β1 can coordinately increase the steady state levels of mRNAs encoding components of the elastic fiber, but through diverse mechanisms. In contrast to LTBP-2, increased elastin expression is achieved by message stabilization. Furthermore, the TGF-B1 signaling pathways differ and while the pathway leading to increased LTBP-2 transcription shares components with those modulating transcription of other genes, it is unlikely to be precisely congruent with any other previously described one.