The Smad4 activation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain.

de Caestecker MP, Yahata T, Wang D, Parks WT, Huang S, Hill CS, Shioda T, Roberts AB, Lechleider RJ
J Biol Chem. 2000 275 (3): 2115-22

PMID: 10636916 · DOI:10.1074/jbc.275.3.2115

Transforming growth factor-beta (TGF-beta) family members signal through a unique set of intracellular proteins called Smads. Smad4, previously identified as the tumor suppressor DPC4, is functionally distinct among the Smad family, and is required for the assembly and transcriptional activation of diverse, Smad-DNA complexes. We previously identified a 48-amino acid proline-rich regulatory element within the middle linker domain of this molecule, the Smad4 activation domain (SAD), which is essential for mediating these signaling activities. We now characterize the functional activity of the SAD. Mutants lacking the SAD are still able to form complexes with other Smad family members and associated transcription factors, but cannot activate transcription in these complexes. Furthermore, the SAD itself is able to activate transcription in heterologous reporter assays, identifying it as a proline-rich transcriptional activation domain, and indicating that the SAD is both necessary and sufficient to activate Smad-dependent transcriptional responses. We show that transcriptional activation by the SAD is p300-dependent, and demonstrate that this activity is associated with a physical interaction of the SAD with the amino terminus of p300. These data identify a novel function of the middle linker region of Smad4, and define the role of the SAD as an important locus determining the transcriptional activation of the Smad complex.

MeSH Terms (21)

Amino Acid Sequence Animals Cell Line COS Cells Cytoplasm DNA-Binding Proteins E1A-Associated p300 Protein Fluorescent Antibody Technique Humans Mice Molecular Sequence Data Nuclear Proteins Precipitin Tests Proline Protein Binding Protein Structure, Tertiary Smad2 Protein Smad4 Protein Trans-Activators Transcription, Genetic Transcriptional Activation

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