How is Type I procollagen synthesis regulated at the gene level during tissue fibrosis.

In response to tissue injury connective tissue synthesis occurs either normally or abnormally, which is mediated by transforming growth factor-beta (TGF-beta) and other growth factors. This article will be primarily concerned with the response of injured tissues at the gene level of Type I procollagen synthesis in response to TGF-beta. This leads to provisional repair, which in turn may lead to involution, remodeling, regeneration, and ultimately repair. Alternately, continuation of provisional repair may lead to fibrosis and ultimately scarring. Scarring of internal organs such as the liver and the lung leads to loss of function and ultimately death. In the case of scarring of skin, this is a cosmetic problem and can be rectified by surgery. Type I procollagen is synthesized by two genes, proalpha1 (Type I) and proalpha2 (Type I) collagen genes. This article will focus on DNA binding sites on these two genes, which regulate the transcription of the specific gene. This article will also define specific cell signaling pathways for the turning on of the proalpha1 and proalpha2 (Type I) collagen genes. This article will address several questions. First, what is the major cytokine acting extracellularly which stimulates the transcription of the proalpha1 and proalpha2 (Type I) collagen genes during tissue fibrosis? Secondly, how are the signals transmitted by the extracellular profibrotic cytokine TGF-beta from the cellular membrane to the nucleus for transcription of the proalpha1 (Type I) and proalpha2 (Type I) collagen genes? Thirdly, what signaling pathways cross-talk with the signaling pathways resulting in the expression of the Type I collagen genes? Fourthly, how does TGF-beta affect extracellular matrix homeostasis? Fifthly, what are the nuclear factors corresponding to the DNA elements required for the promotion of the proalpha1 (Type I) and proalpha2 (Type I) collagen genes? Finally, how are the proalpha1 (Type I) and proalpha2 (Type I) collagen genes coordinately regulated? Strategies will also be presented for reducing fibrosis, which is the result of overexpression of TGF-beta. Copyright 2003 Wiley-Liss, Inc.