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.
Chang
Weizhong
W
Department of Surgery (Plastic Surgery Section), Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8041, USA.
Parra
Macarena
M
Ji
Changhua
C
Liu
Yuan
Y
Eickelberg
Oliver
O
McCarthy
Thomas L
TL
Centrella
Michael
M
D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010294:Parietal Bone; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D051720:Upstream Stimulatory Factors
C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; C508962:Tgfb1 protein, rat; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D051720:Upstream Stimulatory Factors; C497182:Usf1 protein, rat; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II