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CREB binding protein is a required coactivator for Smad-dependent, transforming growth factor beta transcriptional

J N Topper1, M R DiChiara, J D Brown

  • 1Vascular Research Division, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. JTopper@leland.stanford.edu

Proceedings of the National Academy of Sciences of the United States of America
|August 5, 1998
PubMed

Insights

Transforming growth factor-beta (TGF-beta) signaling involves Smad proteins interacting with CREB binding protein (CBP). This interaction is crucial for TGF-beta-induced gene transcription in endothelial cells.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Transcriptional Regulation

Background:

  • The transforming growth factor-beta (TGF-beta) superfamily regulates cardiovascular development and physiology.
  • Smad proteins are key intracellular mediators of TGF-beta superfamily signaling pathways.

Purpose of the Study:

  • To investigate the functional interaction between Smad proteins and the transcriptional coactivator CREB binding protein (CBP).
  • To elucidate the role of Smad-CBP interactions in TGF-beta-mediated transcriptional responses in endothelial cells.

Main Methods:

  • Mammalian two-hybrid assays to detect protein-protein interactions.
  • Biochemical approaches to confirm interactions and map interaction domains.
  • Functional assays using 12S E1A protein and exogenous CBP to assess the role of Smad-CBP interaction in gene transcription.

Main Results:

  • Human Smad2 and Smad4 functionally interact with CREB binding protein (CBP).
  • This interaction is ligand-dependent (TGF-beta) and mediated by Smad transcriptional activation domains.
  • Smad7, a distinct Smad protein, does not interact with CBP.
  • Smad-CBP interaction occurs at the COOH terminus of CBP and is essential for TGF-beta-induced transcription in endothelial cells.

Conclusions:

  • Demonstrates a functional interaction between Smad proteins and CBP, a critical component of the transcriptional machinery.
  • Highlights the importance of Smad-CBP coactivator interactions in regulating TGF-beta transcriptional responses.
  • Suggests that Smad-coactivator interactions serve as a key signaling integration point in endothelial cells.

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