Analysis of signal transduction pathways and nuclear expression control of the human biglycan gene during induction by TGF-beta and repression by TNF-alpha

Biglycan, a small leucine-rich proteoglycan, is functionally involved in the remodeling of the extracellular matrix by regulating collagen assembly and TGF-β activity. Its expression is pathophysiologically altered in organ fibrosis, atherosclerosis, and desmoplastic reactions in carcinoma tissue. Biglycan synthesis is transcriptionally repressed by TNF-α and posttranscriptionally induced by TGF-β at the level of mRNA processing or nuclear export. The aim of this project is to elucidate the molecular mechanisms by which TGF-β and TNF-α exert their effect on biglycan expression. For regulation by TGF-β, the aim is not only to identify and characterize the signal-transducing molecules through which the signal for increased formation of mature biglycan mRNA reaches the cell nucleus, but also to clarify how this growth factor stimulates the accumulation of fully processed mRNA transcripts. In the case of TNF-α, the aim is to examine which cis- and trans-acting elements are involved in TNF-α-induced inhibition of transcription. It is expected that uncovering the molecular mechanisms of action of TGF-β and TNF-α on biglycan synthesis will enable targeted pharmacological interventions to inhibit the formation of fibrosis and desmoplasia, thus better managing clinical problems.