Role of activator protein 1 transcriptional activity in the regulation of gene expression by transforming growth factor beta1 and bone morphogenetic protein 2 in ROS 17/2.8 osteoblast-like cells.
In osteoblastic cells, transforming growth factor beta1 (TGF-beta1) has been found to regulate the expression of a variety of proto-oncogenes including c-fos, c-jun, and junB. The c-fos in particular has been implicated in the mitogenic effect of TGF-beta1. Here, we examined the role of these early response genes in the regulation of osteoblast (OB) gene expression by two members of the TGF-beta superfamily, TGF-beta1 and bone morphogenetic protein 2 (BMP-2). In ROS 17/2.8 cells, TGF-beta1 as well as BMP-2 up-regulated the expression of junB and c-fos messenger RNAs (mRNAs), and this increase was correlated in both cases with an increase in activator protein 1 (AP-1) DNA-binding activity involving JunB and c-Fos proteins. Protein kinase C (PKC)- and protein tyrosine kinase (PTK)-dependent pathways have been implicated in both TGF-beta1 signaling and AP-1 gene regulation. Therefore, using the kinase inhibitors chelerythrine chloride and genistein, we showed that PKC and PTK activities, respectively, participated in TGF-beta1- and BMP-2-induced increases in junB mRNA levels. Similarly, these kinase activities were involved in the stimulatory effect of BMP-2 on c-fos mRNA expression. Using a natural dominant negative for AP-1 transcriptional activity in ROS 17/2.8 cells, we then showed that AP-1 transcription factors mediated TGF-beta1- and BMP-2-regulated expression of the (alpha1) collagen I gene as well as TGF-beta1-regulated expression of the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor. Our data emphasize the role of the AP-1 transcription factor in TGF-beta1 and BMP-2 signaling and highlight the importance of this transcription factor family in the expression of OB genes.
Palcy
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Department of Medicine, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada.
Bolivar
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Goltzman
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D000818:Animals; D015152:Blotting, Northern; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000187:drug effects* / Q000235:genetics; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D015151:Immunoblotting; D066298:In Vitro Techniques; D010006:Osteoblasts / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein; D011233:Precipitin Tests; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C