Smad7 Induces Tumorigenicity by Blocking TGF-beta-induced Growth Inhibition and Apoptosis

Exp Cell Res. 2005 Jul 1;307(1):231-46. doi: 10.1016/j.yexcr.2005.03.009. Epub 2005 Apr 19.

Abstract

Smad proteins play a key role in the intracellular signaling of the transforming growth factor beta (TGF-beta) superfamily of extracellular polypeptides that initiate signaling to regulate a wide variety of biological processes. The inhibitory Smad, Smad7, has been shown to function as intracellular antagonists of TGF-beta family signaling and is upregulated in several cancers. To determine the effect of Smad7-mediated blockade of TGF-beta signaling, we have stably expressed Smad7 in a TGF-beta-sensitive, well-differentiated, and non-tumorigenic cell line, FET, that was derived from human colon adenocarcinoma. Smad7 inhibits TGF-beta-induced transcriptional responses by blocking complex formation between Smad 2/3 and Smad4. While Smad7 has no effect on TGF-beta-induced activation of p38 MAPK and ERK, it blocks the phosphorylation of Akt by TGF-beta and enhances TGF-beta-induced phosphorylation of c-Jun. FET cells expressing Smad7 show anchorage-independent growth and enhance tumorigenicity in athymic nude mice. Smad7 blocks TGF-beta-induced growth inhibition by preventing TGF-beta-induced G1 arrest. Smad7 inhibits TGF-beta-mediated downregulation of c-Myc, CDK4, and Cyclin D1, and suppresses the expression of p21(Cip1). As a result, Smad7 inhibits TGF-beta-mediated downregulation of Rb phosphorylation. Furthermore, Smad7 inhibits the apoptosis of these cells. Together, Smad7 may increase the tumorigenicity of FET cells by blocking TGF-beta-induced growth inhibition and by inhibiting apoptosis. Thus, this study provides a mechanism by which a portion of human colorectal tumors may become refractory to tumor-suppressive actions of TGF-beta that might result in increased tumorigenicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • Blotting, Western
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Neoplastic
  • Growth Inhibitors / antagonists & inhibitors*
  • Growth Inhibitors / pharmacology
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplasms / etiology*
  • Precipitin Tests
  • Retroviridae / genetics
  • Signal Transduction
  • Smad7 Protein
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription, Genetic
  • Transfection
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Transplantation, Heterologous

Substances

  • DNA-Binding Proteins
  • Growth Inhibitors
  • SMAD7 protein, human
  • Smad7 Protein
  • Smad7 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta