Hierarchical model of gene regulation by transforming growth factor beta.
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.
Yang
Yaw-Ching
YC
Departments of Medicine and Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461.
Piek
Ester
E
Zavadil
Jiri
J
Liang
Dan
D
Xie
Donglu
D
Heyer
Joerg
J
Pavlidis
Paul
P
Kucherlapati
Raju
R
Roberts
Anita B
AB
Böttinger
Erwin P
EP
D000818:Animals; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000502:physiology; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D020449:Repetitive Sequences, Amino Acid; D020218:Response Elements; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*
D004268:DNA-Binding Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D020928:Mitogen-Activated Protein Kinases