Robert Beauchamp
Principal Investigator
Last active: 10/31/2018

Smad7 induces tumorigenicity by blocking TGF-beta-induced growth inhibition and apoptosis.

Halder SK, Beauchamp RD, Datta PK
Exp Cell Res. 2005 307 (1): 231-46

PMID: 15922743 · DOI:10.1016/j.yexcr.2005.03.009

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.

MeSH Terms (24)

Animals Apoptosis Blotting, Western Cell Line Cercopithecus aethiops COS Cells DNA-Binding Proteins Dose-Response Relationship, Drug Gene Expression Regulation, Neoplastic Growth Inhibitors Humans Mice Mice, Nude Neoplasms Neoplasm Transplantation Precipitin Tests Retroviridae Signal Transduction Smad7 Protein Trans-Activators Transcription, Genetic Transfection Transforming Growth Factor beta Transplantation, Heterologous

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