Interaction between Smad7 and beta-catenin : importance for transforming growth factor beta-induced apoptosis

• Members of the transforming growth factor beta (TGF-beta) and Wnt/wingless superfamilies regulate cell fate during development and tissue maintenance. Here we report that Smad7 interacts with beta-catenin and lymphoid enhancer binding factor 1/T-cell-specific factor (LEF1/TCF), transcriptional regulators in Wnt signaling, in a TGF-beta-dependent manner. Smad7 was found to be required for TGF-beta1-induced accumulation of beta-catenin and LEF1 in human prostate cancer (PC-3U) cells as well as in human keratinocytes (HaCaT cells). Moreover, when the endogenous Smad7 was repressed by specific small interfering RNA, TGF-beta-induced increase of activated p38, Akt phosphorylated on Ser473, glycogen synthase kinase 3beta phosphorylated on Ser9 was prevented, as well as the TGF-beta-induced association between beta-catenin and LEF1. Notably, the observed physical association of Smad7 and beta-catenin was found to be important for TGF-beta-induced apoptosis, since suppression of beta-catenin expression by small interfering RNA decreased the apoptotic response to TGF-beta.

Nyckelord

Animals

Apoptosis/drug effects/*physiology

COS Cells

Cell Fractionation

Cercopithecus aethiops

Cytoskeletal Proteins/*metabolism

DNA-Binding Proteins/*metabolism

Glycogen Synthase Kinase 3/metabolism

Humans

Male

Mice

Phosphorylation/drug effects

Prostatic Neoplasms/metabolism

Protein Binding/drug effects

Protein-Serine-Threonine Kinases/metabolism

Proto-Oncogene Proteins/metabolism

RNA; Small Interfering/metabolism

Research Support; Non-U.S. Gov't

Serine/metabolism

Trans-Activators/*metabolism

Transcription Factors/*metabolism

Transforming Growth Factor beta/*pharmacology

Tumor Cells; Cultured

p38 Mitogen-Activated Protein Kinases/metabolism

Publikations- och innehållstyp

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