Transcriptional and post-transcriptional regulation of transforming growth factor beta type II receptor expression in osteoblasts.

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.