Inhibition of the TGF-Beta Tumor Suppression Pathway Through Repression of Smad Dependent Transcription
Abstract
TGF Beta and its downstream Smad proteins play important roles in the regulation of cell growth and differentiation. The long-term goal of this project is to characterize the role of TGF Beta signaling in the function of normal and cancerous breast tissues and cells. We have previously identified a nuclear proto-oncoprotein SnoN as an important negative regulator of Smad function. In normal TGF Beta responsive cells, the expression of SnoN is tightly regulated by TGF Beta signaling, and we found that Smad3 can cause a rapid degradation of SnoN. Here we show that Smad2- or Smad3-induced degradation of SnoN requires the ubiquitin-dependent proteasome and can be mediated by the anaphase promoting complex (APC) and the UbcH5 family of ubiquitin conjugating enzymes. Smad 3 interacts with both the APC and SnoN, resulting in the recruitment of the APC to SnoN and subsequent ubiquitination of SnoN in a destruction box dependent manner. in addition to the destruction box, efficient degradation of SnoN also requires the Smad3 binding site in SnoN as well as key lysine residues necessary for ubiquitin attachment. Our studies therefore elucidate and important pathway for the degradation of SnoN and reveal a novel role of the APC in regulation of TGF Beta signaling.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2002
- Accession Number
- ADA410251
Entities
People
- Deng Pan
- Kunxin Luo
- Shannon Stroschein
Organizations
- University of California, Berkeley