Cutroneo Kenneth R
College of Medicine, University of Vermont, Burlington, Vermont 05405-0068, USA.
J Cell Biochem. 2003 Sep 1;90(1):1-5. doi: 10.1002/jcb.10599.
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.
针对组织损伤，结缔组织合成会正常或异常发生，这由转化生长因子-β（TGF-β）和其他生长因子介导。本文将主要关注受损组织在I型前胶原合成基因水平上对TGF-β的反应。这会导致临时修复，进而可能导致退化、重塑、再生，并最终实现修复。另外，临时修复的持续可能会导致纤维化并最终形成瘢痕。肝脏和肺等内脏器官的瘢痕形成会导致功能丧失并最终导致死亡。对于皮肤瘢痕，这是一个美容问题，可以通过手术矫正。I型前胶原由两个基因，即原α1（I型）和原α2（I型）胶原基因合成。本文将聚焦于这两个基因上调节特定基因转录的DNA结合位点。本文还将定义开启原α1和原α2（I型）胶原基因的特定细胞信号通路。本文将探讨几个问题。首先，在组织纤维化过程中，细胞外刺激原α1和原α2（I型）胶原基因转录的主要细胞因子是什么？其次，细胞外促纤维化细胞因子TGF-β如何从细胞膜将信号传递至细胞核以转录原α1（I型）和原α2（I型）胶原基因？第三，哪些信号通路与导致I型胶原基因表达的信号通路相互作用？第四，TGF-β如何影响细胞外基质稳态？第五，与促进原α1（I型）和原α2（I型）胶原基因所需的DNA元件相对应的核因子是什么？最后，原α1（I型）和原α2（I型）胶原基因如何协同调节？还将提出减少因TGF-β过表达导致的纤维化的策略。
