Hierarchical model of gene regulation by transforming growth factor beta

Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10269-74. doi: 10.1073/pnas.1834070100. Epub 2003 Aug 20.


Transforming growth factor betas (TGF-betas) regulate key aspects of embryonic development and major human diseases. Although Smad2, Smad3, and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs) have been proposed as key mediators in TGF-beta signaling, their functional specificities and interactivity in controlling transcriptional programs in different cell types and (patho)physiological contexts are not known. We investigated expression profiles of genes controlled by TGF-beta in fibroblasts with ablations of Smad2, Smad3, and ERK MAPK. Our results suggest that Smad3 is the essential mediator of TGF-beta signaling and directly activates genes encoding regulators of transcription and signal transducers through Smad3/Smad4 DNA-binding motif repeats that are characteristic for immediate-early target genes of TGF-beta but absent in intermediate target genes. In contrast, Smad2 and ERK predominantly transmodulated regulation of both immediate-early and intermediate genes by TGF-beta/Smad3. These results suggest a previously uncharacterized hierarchical model of gene regulation by TGF-beta in which TGF-beta causes direct activation by Smad3 of cascades of regulators of transcription and signaling that are transmodulated by Smad2 and/or ERK.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • DNA-Binding Proteins / physiology
  • Gene Expression Regulation*
  • Genes, Immediate-Early
  • Mice
  • Mitogen-Activated Protein Kinases / physiology
  • Models, Genetic
  • Oligonucleotide Array Sequence Analysis
  • Repetitive Sequences, Amino Acid
  • Response Elements
  • Signal Transduction
  • Smad2 Protein
  • Smad3 Protein
  • Trans-Activators / physiology
  • Transforming Growth Factor beta / physiology*


  • DNA-Binding Proteins
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Mitogen-Activated Protein Kinases