Both the Smad and p38 MAPK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-beta and bone morphogenetic protein.
The Runx family of transcription factors plays pivotal roles during normal development and in neoplasias. In mammals, Runx family genes are composed of Runx1 (Pebp2alphaB/Cbfa2/Aml1), Runx2 (Pebp2alphaA/Cbfa1/Aml3) and Runx3 (Pebp2alphaC/Cbfa3/Aml2). Runx1 and Runx3 are known to be involved in leukemogenesis and gastric carcinogenesis, respectively. Runx2, on the other hand, is a common target of transforming growth factor-beta1 (TGF-beta1) and bone morphogenetic protein-2 (BMP-2) and plays an essential role in osteoblast differentiation. Runx2 is induced by the receptor-activated Smad; Runx2 mediates the blockage of myogenic differentiation and induces osteoblast differentiation in C2C12 pluripotent mesenchymal precursor cells. However, Smad does not directly induce Runx2 expression; an additional step of de novo protein synthesis is required. Here we report that Smad-induced junB functions as an upstream activator of Runx2 expression. Furthermore, not only the Smad pathway but also the mitogen-activated protein kinase (MAPK) cascades are involved in the induction of Runx2 by TGF-beta1 and BMP-2. Our results demonstrate that following TGF-beta and BMP induction, both the Smad and p38 MAPK pathways converge at the Runx2 gene to control mesenchymal precursor cell differentiation.
Lee
Kyeong-Sook
KS
Department of Biochemistry, School of Medicine, Chungbuk National University, Cheongju, 361-763, South Korea.
Hong
Seung-Hyun
SH
Bae
Suk-Chul
SC
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002454:Cell Differentiation; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009363:Neoplasm Proteins; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051785:Smad Proteins; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D051785:Smad Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases