Smad3: a key player in pathogenetic mechanisms dependent on TGF-beta.
Transforming growth factor-beta (TGF-beta), a key player in a large variety of physiological and disease processes, signals through transmembrane receptor serine/threonine kinases to activate novel signaling intermediates called Smad proteins, which then modulate transcription of target genes. We have utilized mice with a targeted deletion of Smad3, one of two homologous proteins involved in signaling from TGF-beta/activin, to investigate the function of this particular pathway in transducing such effects of TGF-beta. The dramatic results of the absence of Smad3 on parameters of healing of cutaneous wounds, such as reepithelialization and influx of inflammatory cells, as well as on fibrosis as modeled by radiation fibrosis of skin in mice, suggest that signaling flux through Smad3 is critical for chemotactic activity of TGF-beta, inhibitory effects of TGF-beta on keratinocyte proliferation and migration, and chemoattraction and elaboration of extracellular matrix by fibroblasts in fibrotic diseases. We recently identified a novel molecule, TLP for TRAP-1-like protein, which selectively interferes with Smad3 signaling, and are currently investigating whether levels of this protein might be altered in disease to change the relative flow of information from Smad2 and Smad3.
Roberts
Anita B
AB
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20895-5055, USA. robertsa@dce41.nci.nih.gov
Russo
Angelo
A
Felici
Angelina
A
Flanders
Kathleen C
KC
D000818:Animals; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004198:Disease Susceptibility; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014945:Wound Healing
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