Chang Weizhong, Parra Macarena, Ji Changhua, Liu Yuan, Eickelberg Oliver, McCarthy Thomas L, Centrella Michael
Department of Surgery (Plastic Surgery Section), Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8041, USA.
Gene. 2002 Oct 16;299(1-2):65-77. doi: 10.1016/s0378-1119(02)01013-2.
Variations in transforming growth factor beta (TGF-beta) activity depend on the expression of specific receptors in normal as well as transformed cells. For example, in addition to mutations in TGF-beta type II receptor (TbetaRII) that abrogate normal TGF-beta function, its expression decreases during the transition from replication to extracellular matrix production, or in response to other growth regulators in bone. Therefore, to understand how TbetaRII expression is controlled, we cloned the rat TbetaRII gene promoter and defined basic aspects of its structure and activity. Among several cis-acting elements, mutations within an upstream E-box that specifically binds USF nuclear factors or a downstream Sp1 binding site significantly reduced TbetaRII promoter activity in primary cultures of fetal rat osteoblasts. Treatment with bone morphogenetic protein 2 (BMP-2), which induces further osteoblast differentiation, significantly reduced cell surface TbetaRII. However, BMP-2 did not alter TbetaRII promoter activity, steady state TbetaRII mRNA, or total TbetaRII protein, but caused an intracellular relocation of TbetaRII. Select transcriptional elements thus regulate TbetaRII gene expression, whereas post-translational events controlled by BMP-2 rapidly modify the amount of TbetaRII protein on the bone cell surface. Consequently, several processes can alter functional TbetaRII levels in order to regulate the biological effects of this important growth factor.
转化生长因子β（TGF-β）活性的变化取决于正常细胞和转化细胞中特定受体的表达。例如，除了II型TGF-β受体（TbetaRII）的突变会消除正常的TGF-β功能外，在从复制到细胞外基质产生的转变过程中，或者响应骨骼中的其他生长调节因子时，其表达会降低。因此，为了了解TbetaRII的表达是如何被控制的，我们克隆了大鼠TbetaRII基因启动子，并确定了其结构和活性的基本方面。在几个顺式作用元件中，上游特异性结合USF核因子的E盒或下游Sp1结合位点内的突变显著降低了胎鼠成骨细胞原代培养物中TbetaRII启动子的活性。用诱导进一步成骨细胞分化的骨形态发生蛋白2（BMP-2）处理后，细胞表面的TbetaRII显著减少。然而，BMP-2并没有改变TbetaRII启动子的活性、稳态TbetaRII mRNA或总TbetaRII蛋白，但导致了TbetaRII的细胞内重新定位。因此，特定的转录元件调节TbetaRII基因的表达，而由BMP-2控制的翻译后事件迅速改变了骨细胞表面TbetaRII蛋白的数量。因此，几个过程可以改变功能性TbetaRII的水平，以调节这种重要生长因子的生物学效应。
