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

Oncogene. 2002 Oct 17;21(47):7156-63. doi: 10.1038/sj.onc.1205937.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / pharmacology*
  • Cell Differentiation
  • Cell Line
  • Core Binding Factor Alpha 1 Subunit
  • Core Binding Factor alpha Subunits
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation
  • MAP Kinase Signaling System
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neoplasm Proteins*
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA, Messenger / metabolism
  • Smad Proteins
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / pharmacology*
  • p38 Mitogen-Activated Protein Kinases


  • Bone Morphogenetic Proteins
  • Core Binding Factor Alpha 1 Subunit
  • Core Binding Factor alpha Subunits
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Smad Proteins
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases